Serine protease inhibitors

ABSTRACT

Compounds having the structure shown below wherein A, B, N 1 , N 2 , X, Y, Q, R 2 , R 5  and R 6  are as defined herein are useful to inhibit serine protease enzymes, such as TF/factor VIIa factor Xa, thrombin and kallikrein. These compounds may be used in methods of preventing and/or treating clotting disorders.

This application is a national phase of International applicationPCT/US00/00673, filed Jan. 11, 2000, and claims priority to provisionalU.S. patent applications Nos. 60/115772, filed Jan. 13, 1999, and60/152,029, filed Sep. 1, 1999.

FIELD OF THE INVENTION

In one aspect, the invention relates to novel compounds which areinhibitors of Tissue Factor (TF)/factor VIIa, factor VIIa, factor Xa,thrombin and/or kallikrein, as well as compositions containing thesecompounds. The compounds are useful for inhibiting these factors and fortreating disorders mediated thereby. For example, the compounds areuseful for preventing thrombosis or treating abnormal thrombosis in amammal by inhibiting TF/factor VIIa, factor Xa, thrombin and/orkallikrein.

BACKGROUND OF THE INVENTION

Normal haemeostasis is the result of a complex balance between theprocesses of clot initiation, formation and clot dissolution. Thecomplex interactions between blood cells, specific plasma proteins andthe vascular surface, maintain the fluidity of blood unless injury andblood loss occurs.

Many significant disease states are related to abnormal haemeostasis.For example, local thrombus formation due to the rupture ofatherosclerotic plaque is a major cause of acute myocardial infarctionand unstable angina. Treatment of an occlusive coronary thrombus byeither thrombolytic therapy or percutaneous angioplasty may beaccompanied by acute thrombolytic reclosure of the affected vessel.Furthermore, a high percentage of patients undergoing surgery,particularly in the lower extremities, suffer thrombus formation in thevenous vascular system which results in reduced blood flow to theaffected area.

There continues to be a need for safe and effective therapeuticanticoagulants to limit or prevent thrombus formation.

Blood coagulation is vital for the containment of bodily fluids upontissue injury and is an important component of host defense mechanisms.Coagulation or clotting involves the sequential activation of multiplezymogens in a process leading to thrombin generation and the conversionof fibrinogen to an impermeable cross-linked fibrin clot. Thrombinproduction is the result of a blood coagulation cascade which has beenintensively studied and increasingly characterized. See for example,Lawson, J. H., et al. (1994) J. Biol. Chem. 269:23357. The coagulationreactions of this cascade involve initiation, amplification andpropagation phases. Additionally, the cascade has been divided intoextrinsic and intrinsic pathways. The intrinsic pathway involves factorsXII, XI, and IX and leads to the formation of a complex of factor IXawith its cofactor, factor VIIIa. This complex converts factor X to Xa.Factor Xa is an enzyme which forms a complex with its cofactor, factorVa, and rapidly converts prothrombin to thrombin. Thrombin convertsfibrinogen to fibrin monomers which polymerize to form a clot. Theextrinsic pathway involves factor VIIa and tissue factor, which form acomplex (TF/factor VIIa), and convert factor X to Xa. As in theintrinsic pathway, factor Xa converts prothrombin to thrombin.

Thrombin (factor IIa), as noted above, occupies a central position inthe coagulation cascade by converting fibrinogen to fibrin.Consequently, substantial synthetic efforts have been directed to thedevelopment of thrombin inhibitors. See, for example, U.S. Pat. No.5,656,600; U.S. Pat. No. 5,656,645; U.S. Pat. No. 5,670,479; U.S. Pat.No. 5,646,165; U.S. Pat. No. 5,658,930 and WO 97/30073. Additionalcompounds which have been prepared as synthetic thrombin inhibitors areN-arylsulfinated phenylalanine amides.

Known inhibitors of factor Xa include bisamidine compounds (Katakura, S.(1993) Biochem. Biophys. Res. Commun., 197:965) and compounds based onthe structure of arginine (WO 93/15756; WO 94/13693). Phenyl andnaphthylsulfonamides have also been shown to be factor Xa inhibitors (WO96/10022; WO 96/16940; WO 96/40679).

TF/factor VIIa is a serine protease complex that participates in bloodcoagulation by activating factor X and/or factor IX. Factor VIIa isproduced from its produced from its precursor, factor VII, which issynthesized in the liver and secreted into the blood where it circulatedas a single chain glycopeptide. The cDNA sequence for factor VII hasbeen characterized (Hagen et al., 1986, Proc. Natl. Acad. Sci. U.S.A.,83:2412-2416).

A variety of natural and synthetic inhibitors of TF/factor VIIa areknown and have varying potency and selectivity. Tissue factor pathwayinhibitor (TFPI; Broze, 1995, Thromb. Haemostas., 74:90) and nematodeanticoagulant peptide c2 (NAPc2; Stanssens et al., 1996, Proc. Natl.Acad. Sci. U.S.A., 93:2149) bind factor Xa prior to the formation of aquaternary inhibitory complex with the TF/factor VIIa complex. Smallprotein direct inhibitors (Dennis et al, 1994, J. Biol. Chem., 35:22137)and inactive forms of TF/factor VIIa are also known (Kirchhofer et al,1995, Arteriosclerosis, Thrombosis and Vascular Biol., 15:1098; Jang etal, 1995, Circulation, 92:3041). Additionally, synthetic peptides andsoluble forms of mutant TF which retain binding affinity but havereduced cofactor activity have been prepared (Roenning et al, 1996,Thromb. Res., 82:73; Kelley et al, 1997, Blood, 89:3219). U.S. Pat. No.5,679,639 describes polypeptides and antibodies which inhibit serineprotease activity. U.S. Pat. No. 5,580,560 describes a mutant factorVIIa which has an improved half-life U.S. Pat. No. 5,504,067 and U.S.Pat. No. 5,504,064 describe a truncated TF for the treatment ofbleeding. Kunitz domain-tissue factor fusion proteins have also beenshown to be bifunctional anticoagulants (Lee et al, 1997, Biochemistry,36:5607-5611). The TF/factor VIIa complex has been indicated as anattractive target for the development of inhibitors based on adissociation between surgical bleeding and prevention of intravascularthrombosis (Harker et al, 1995, Thromb. Haemostas., 74:464).

Compounds which block or inhibit enzymes in the coagulation cascade aretherapeutically useful in treating or preventing thrombosis in a mammalsuspected of having a condition characterized by abnormal thrombosis.For example, with respect to arterial vasculature, abnormal thrombusformation due to deterioration of an established atherosclerotic plaqueis a major cause of acute myocardial infarction and unstable angina.Treatment of an occlusive coronary thrombus by thrombolytic therapy orpercutaneous transluminal coronary angioplasty (PTCA) may be accompaniedby reclosure of the vessel. In the venous vasculature, many patientsundergoing surgery, particularly in the abdominal and lower bodyregions, experience thrombus formation which reduces blood flow and canlead to a pulmonary embolism. Disseminated intravascular coagulopathy inboth the venous and arterial systems occurs commonly during septicshock, some viral infections, and cancer and may lead to rapid andwidespread thrombus formation and organ failure.

PTCA and recanalization are favored procedures for treating occludedvessels. However arterial thrombosis following these procedures remainsa leading cause of failure. Heparin, the most widely used anticoagulant,has not been shown to be entirely effective in the treatment andprevention of acute arterial thrombosis or rethrombosis.

The synthesis and development of small molecule inhibitors based on theknown three-dimensional structure of proteins is a challenge of moderndrug development. Many thrombin inhibitors have been designed to have ahirudin-type structure. Stubbs and Bode, Current Opinion in StructuralBiology 1994, 4:823-832. New synthetic thrombin inhibitors, as well asinhibitors of factor Xa and TF/factor VIIa, are reported. See, forexample, Annual Reports in Medicinal Chemistry, 1995-1997, AcademicPress, San Diego, Calif.

U.S. Pat. No. 5,589,173 describes the use of a tissue factor antagonistand a thrombolytic agent to treat myocardial infarction.

U.S. Pat. No. 5,399,487 describes naphthalenesulfonamides which areuseful for determining proteolytic enzyme activity or as enzymeinhibitors.

A need continues to exist for compounds which are effective inhibitorsof enzymes in the coagulation cascade and which exhibit improvedinhibitory activity and/or selectivity towards selected enzymes in thecascade.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelcompounds which inhibit factors/enzymes in the coagulation cascade andwhich are useful to prevent or treat thrombus formation in artertial orvenous vessels. These compounds are useful as coagulation factorinhibitors and as anticoagulants in general.

In one embodiment, an object of the invention is to provide inhibitorswhich inhibit factor VIIa, TF/factor VIIa selectively relative to factorXa, thrombin or kallikrein. The compounds of this embodiment preferablyinhibit TF/factor VIIa about one order of magnitude (10×), morepreferably about two orders of magnitude(100×), even more preferablyabout three orders of magnitude (100×), better than they inhibit factorXa, thrombin and/or kallikrein.

In another embodiment, an object of the invention is to providecompounds which specifically inhibit factor Xa relative to theinhibition of factor VIIa, TF/factor VIIa, thrombin or kallikrein. Thecompounds of this embodiment preferably inhibit factor Xa about oneorder of magnitude (10×), more preferably about two orders of magnitude(100×), even more preferably about three orders of magnitude (1000×),better than they inhibit TF/factor VIIa, thrombin and/or kallikrein.

In another embodiment, a specific object of the invention is to providecompounds which inhibit thrombin relative to inhibition of factor VIIa,TF/factor VIIa, Xa, or kallikrein. The compounds of this embodimentpreferably inhibit factor thrombin about one order of magnitude (10×),more preferably about two orders of magnitude(100×), even morepreferably about three orders of magnitude (1000×), better than theyinhibit TF/factor VIIa, factor Xa and/or kallikrein.

A further object of the invention is to provide a method of inhibitingTF/factor VIIa, Xa or thrombin activity by contacting these enzymes withan effective inhibitory amount of the novel inhibitors of the presentinvention or a composition containing these compounds. A further objectis to provide a method of treating a TF/factor VIIa, Xa or thrombinmediated disorder by administering to a mammal in need of such treatmentan effective amount of one of the compounds of the invention or acomposition containing the compound. An additional object is to providea method of preventing thrombosis or treating abnormal thrombosis byadministering to a mammal in need of such treatment an effective amountof one of the compounds of the invention or a composition containing thecompound and a carrier or excipient.

These and other objects which will become apparent in the course of thefollowing description have been achieved by the compounds of the presentinvention having the structure shown below:

where

A and B are independently CH, CR₃ or N;

X is C═O or (CR_(4a)R_(4b))_(m) where m=1 or 2;

Y is S(O)_(n)—R₁ where n=1 or 2, S(O)_(n)—NR₂R₂ where n=1 or 2,S(O)_(n)—OR₂ where n=1 or 2, C(O)R₁, C(SR₁, C(O)—OR₁, C(O)—NR₂R₂;

N₁ and N₂ are nitrogen atoms;

Q and R₁ are independently

(1) optionally substituted alkyl having 1 to about 10 carbon atoms;

(2) optionally substituted aralkyl containing an aryl moiety having 6 toabout 10 ring carbon atoms bonded to an alkyl moiety containing 1 toabout 10 carbon atoms;

(3) optionally substituted heteroaralkyl containing a heteroaryl moietyhaving 5 to about 10 ring atoms bonded to an alkyl moiety having 1 toabout 10 carbon atoms;

(4) optionally substituted carbocycloalkyl containing a carbocyclylmoiety having 3 to about 10 ring carbon atoms bonded to an alkyl moietyhaving 1 to about 10 carbon atoms;

(5) optionally substituted heterocycloalkyl containing a heterocyclylmoiety having 3 to about 10 ring atoms bonded to an alkyl moiety having1 to about 10 carbon atoms;

(6) optionally substituted alkenyl having 2 to about 10 carbon atoms;

(7) optionally substituted aralkenyl containing an aryl moiety having 5to about 10 ring atoms bonded to an alkenyl moiety having 2 to about 10carbon atoms;

(8) optionally substituted heteroaralkenyl containing a heteroarylmoiety having 5 to about 10 ring atoms bonded to an alkenyl moietyhaving 2 to about 10 carbon atoms;

(9) optionally substituted carbocycloalkenyl containing a carbocyclylmoiety having 3 to about 10 ring carbon atoms bonded to an alkenylmoiety having 2 to about 10 carbon atoms;

(10) optionally substituted heterocycloalkenyl containing a heterocyclylmoiety having 3 to about 10 ring atoms bonded to an alkenyl moietyhaving 2 to about 10 carbon atoms;

(11) optionally substituted aryl having 6 to about 10 ring carbon atoms;

(12) optionally substituted heteroaryl having 5 to about 10 ring atomswith ring atoms selected from carbon atoms and heteroatoms, where theheteroatoms are nitrogen, oxygen or sulfur;

(13) optionally substituted carbocyclyl having 3 to about 10 ring carbonatoms;

(14) optionally substituted heterocyclyl having 3 to about 10 ring atomswith ring atoms selected from carbon atoms and heteroatoms, where theheteroatoms are nitrogen, oxygen or sulfur;

each R₂ is, independently, H, alkyl, substituted alkyl, C(O)R₇ orC(NH)R₇, or N₁R₂ and N₂R₂ are together form the group N₁—CO—N₂;

R₃ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen or OH;

R_(4a) and R₅ are, independently, a member selected from the groupconsisting of H, unsubstituted or substituted alkyl, unsubstituted orsubstituted alkoxyalkyl, unsubstituted or substituted haloalkyl,unsubstituted or substituted aryl, alkyl-OR₇, alkyl-NR₇R₈,alkyl-OC(O)R₇, alkyl-C(O)OR₇, alkyl-C(O)R₇, OC(O)R₇, C(O)OR₇, C(O)R₇ andmembers in which the alkyl, R₇ or R₈ is substituted with 1-3 F, Cl, Br,I, OR₇, SR₇, NR₇R₈, OC(OR₇), C(O)OR₇, C(O)R₇, C(O)NR₇R₈, NHC(NH)NH₂,PO₃, unsubstituted or substituted indolyl or unsubstituted orsubstituted imidazolyl groups;

R_(4b) is H, alkyl, or substituted alkyl;

each R₆ is independently selected from the group selected from H, C₁-C₆alkyl, C₁-C₆ alkyl-OR₇, C₁-C₆ alkyl-N R₇R₈, C₁-C₆ haloalkyl, halo,cyano, OR₇, SR₇, NR₇R₈, C(O)OR₇, C(O)R₇ and OC(O)R₇;

R₇ and R₈ are independently H or C₁-C₆ alkyl; and acid and base additionsalts and prodrugs thereof.

Additionally, the objects of the invention are achieved by compositionscontaining these compounds and the methods described below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS DEFINITIONS

The term “factor VIIa, TF/factor VIIa, factor Xa, thrombin or kallikreinmediated disorder” means a disease or physiological condition involvingclotting of the blood and in which inhibition of one or more of theseenzymes reduces or eliminates at least one of the physiological symptomsof the disease or condition.

The term “thrombosis” means the development of or formation of a bloodclot or thrombus in a blood vessel of a mammal or in a synthetic vessel,such as a plastic or glass tube or vial. A thrombus which has detachedfrom its original site and is found in another site is called athrombotic embolus.

The term “abnormal thrombosis” means thrombosis occurring in a mammalwhich is contrary to the good health of the mammal.

The term “alkyl”, used alone or as part of another term, means abranched or unbranched, saturated aliphatic hydrocarbon group, havingthe number of carbon atoms specified, or if no number is specified,having up to and including 12 carbon atoms. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl,n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl,2-methylhexyl, and the like. The terms “lower alkyl” “C₁-C₆ alkyl” and“alkyl of 1 to 6 carbon atoms” are synonymous and used interchangeably.Preferred “C₁-C₆ alkyl” groups are methyl, ethyl, 1-propyl, isopropyl,1-butyl or sec-butyl.

The terms “substituted alkyl” or “substituted C_(n)-C_(m) alkyl” where mand n are integers identifying the range of carbon atoms contained inthe alkyl group, denotes the above alkyl groups that are substituted byone, two or three halogen (F, Cl, Br, I), trifluoromethyl, hydroxy,unsubstituted and substituted C₁-C₇ alkoxy, protected hydroxy, amino(including alkyl and dialkyl amino), protected amino, unsubstituted andsubstituted C₁-C₇ acyloxy, unsubstituted and substituted C₃-C₇heterocyclyl, unsubstituted and substituted phenoxy, nitro, carboxy,protected carboxy, unsubstituted and substituted carboalkoxy,unsubstituted and substituted acyl, carbamoyl, carbamoyloxy, cyano,methylsulfonylamino, unsubstituted and substituted benzyloxy,unsubstituted and substituted C₃-C₆ carbocyclyl or C₁-C₄ alkoxy groups.The substituted alkyl groups may be substituted once (preferably), twiceor three times with the same or with different substituents.

Examples of the above substituted alkyl groups include, but are notlimited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl,propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl,trifuoroethyl, trifluoropropyl, carboxypropyl, 2-aminopropyl,alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl,methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl,chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl,2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl and thelike. The alkyl group may also be substituted with a carbocyclo group.Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,and cyclohexylmethyl groups, as well as the corresponding -ethyl,-propyl, -butyl, -pentyl, -hexyl groups, etc. A preferred group ofexamples within the above group includes the substituted methyl group,e.g. a methyl group substituted by the same substituents as the“substituted C_(n)-C_(m) alkyl” group. Examples of the substitutedmethyl group include groups such as hydroxymethyl, protectedhydroxymethyl (e.g. tetrahydropyranyloxymethyl), acetoxymethyl,carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl,bromomethyl and iodomethyl.

The term “alkoxy” denotes groups having the number of carbon atomsspecified such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,s-butoxy, t-butoxy and like groups. The term “substituted alkoxy” meansthese alkoxy groups substituted by the same substituents as the“substituted C_(n)-C_(m) alkyl” group, for example,2,2,2-trifluoroethoxy, 2,2,2-trifluoropropoxy, etc.

The term “acyloxy” denotes herein carboacyloxy groups having thespecified number of carbon atoms such as formyloxy, acetoxy,propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, andthe like. The term “substituted acyloxy” means these acyloxy groupssubstituted by the same substituents as the “substituted C_(n)-C_(m)alkyl” group.

The term “alkylcarbonyl”, “alkanoyl” and “acyl” are used interchangeablyherein encompass groups having the specified number of carbon atoms suchas formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl,benzoyl and the like.

The terms “carbocyclyl”, “carbocyclylic” and “carbocyclo” alone and whenused as a moiety in a complex group such as a carbocycloalkyl group,refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14carbon atoms and preferably 3 to 7 carbon atoms. Preferred carbocyclicgroups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexylgroups. The terms “substituted carbocyclyl” and “carbocyclo” mean thesegroups substituted by the same substituents as the “substitutedC_(n)-C_(m) alkyl” group.

A “carbocycloalkyl” group is a carbocyclo group as defined abovecovalently bonded to an alkyl group as defined above.

The term “alkenyl” means a branched or unbranched hydrocarbon grouphaving the number of carbon atoms designated containing one or morecarbon-carbon double bonds, each double bond being independently cis,trans, or a nongeometric isomer. The term “substituted alkenyl” meansthese alkenyl groups substituted by the same substituents as the“substituted C_(n)-C_(m) alkyl” group.

The term “alkynyl” means a branched or unbranched hydrocarbon grouphaving the number of carbon atoms designated containing one or morecarbon-carbon triple bonds. The term “substituted alkynyl” means thesealkynyl groups substituted by the same substituents as the “substitutedC_(n)-C_(m) alkyl” group.

The terms “alkylthio” and “C₁-C₁₂ substituted alkylthio” denote C₁-C₁₂alkyl and C₁-C₁₂ substituted alkyl groups, respectively, attached to asulfur which is in turn the point of attachment for the alkylthio orsubstituted alkylthio group to the group or substituent designated.

The term “aryl” when used alone or as part of another term means ahomocyclic aromatic group whether or not fused having the number ofcarbon atoms designated or if no number is designated, up to 14 carbonatoms. Preferred aryl groups include phenyl, naphthyl, biphenyl,phenanthrenyl, naphthacenyl, and the like (see e.g. Lang's Handbook ofChemistry (Dean, J. A., ed) 13^(th) ed. Table 7-2 [1985]).

The term “substituted phenyl” or “substituted aryl” denotes a phenylgroup or aryl group substituted with one, two, three, four or five,preferably 1-2, 1-3 or 1-4 substituents chosen from halogen (F, Cl, Br,I), hydroxy, protected hydroxy, cyano, nitro, alkyl (preferably C₁-C₆alkyl), alkoxy (preferably C₁-C₆ alkoxy), benzyloxy, carboxy, protectedcarboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl,protected hydroxymethyl, aminomethyl, protected aminomethyl,trifluoromethyl, alkylsulfonylamino, arylsulfonylamino,heterocyclylsulfonylamino, heterocyclyl, aryl, or other groupsspecified. One or methyne (CH) and/or methylene (CH₂) groups in thesesubstituents may in turn be substituted with a similar group as thosedenoted above. Examples of the term “substituted phenyl” includes but isnot limited to a mono- or di(halo)phenyl group such as 4-chlorophenyl,2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl,3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl,3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- ordi(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl,2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and thelike; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenylgroup, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenylgroup such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; amono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3,4-diethoxyphenyl, 3-ethoxy-4-isopropoxyphenyl,3-ethoxy-s-butoxyphenyl, 3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl,4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl andthe like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or(protected carboxy)phenyl group such 4-carboxyphenyl; a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenylgroups where 1, 2, or 3 of the substituents are different, for example3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Preferredsubstituted phenyl groups include the 3-methoxyphenyl, 3-ethoxy-phenyl,4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl,3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenylgroups. Also, the term “substituted phenyl” represents phenyl groupshaving an aryl, phenyl or heteroaryl group fused thereto. The fused ringmay also be substituted with any, preferably 1, 2 or 3, of thesubstituents identified above for “substituted alkyl” groups.

The term “aralkyl” means one, two, or three aryl groups having thenumber of carbon atoms designated, appended to an alkyl group having thenumber of carbon atoms designated including but not limited to; benzyl,napthylmethyl, phenethyl, benzhydryl (diphenylmethyl), trityl, and thelike. A preferred arylalkyl group is the benzyl group.

The term “substituted aralkyl” denotes an alkyl group, preferably aC₁-C₈alkyl group, substituted at any carbon with an aryl group,preferably a C₆-C₁₀aryl group, bonded to the alkyl group through anyaryl ring position and substituted on the alkyl portion with one, two orthree groups chosen from halogen (F, Cl, Br, I), hydroxy, protectedhydroxy, amino, protected amino, C₁-C₇acyloxy, nitro, carboxy, protectedcarboxy, carbamoyl, carbamoyloxy, cyano, C₁-C₆alkylthio,N-(methylsulfonylamino) or C₁-C₄alkoxy. Optionally the aryl group may besubstituted with one, two, three, four or five groups chosen fromhalogen, hydroxy, protected hydroxy, nitro, C₁-C₆alkyl, C₁-C₆alkoxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, or an N-(methylsulfonylamino) group. As before, when eitherthe C₁-C₈ alkyl portion or the aryl portion or both are disubstituted,the substituents can be the same or different. This group may alsoappear as the substituted aralkyl moiety of a substituted aralkoxygroup.

Examples of the term “substituted aralkyl” and this group when it occursin a “substituted aralkoxy” group include groups such as2-phenyl-1-chloroethyl, 1-phenyl-1-chloromethyl, 1-phenyl-1-bromomethyl,2-(4-methoxyphenyl)ethyl, 2,6-dihydroxy-4-phenyl(n-hexyl),5-cyano-3-methoxy-2-phenyl(n-pentyl), 3-(2,6-dimethylphenyl)n-propyl,4-chloro-3-aminobenzyl, 6-(4-methoxyphenyl)-3-carboxy(n-hexyl),5-(4-aminomethyl phenyl)-3-(aminomethyl)(n-pentyl), and the like.

The term “carboxy-protecting group” as used herein refers to one of theester derivatives of the carboxylic acid group commonly employed toblock or protect the carboxylic acid group while reactions are carriedout on other functional groups on the compound. Examples of suchcarboxylic acid protecting groups include 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4′-dimethoxybenzhydryl,2,2′,4,4′-tetramethoxybenzhydryl, alkyl such as methyl, ethyl,isopropyl, t-butyl or t-amyl, trityl, 4-methoxytrityl,4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl,trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The speciesof carboxy-protecting group employed is not critical so long as thederivatized carboxylic acid is stable to the condition of subsequentreaction(s) on other positions of the molecule and can be removed at theappropriate point without disrupting the remainder of the molecule. Inparticular, it is important not to subject a carboxy-protected moleculeto strong nucleophilic bases or reductive conditions employing highlyactivated metal catalysts such as Raney nickel. (Such harsh removalconditions are also to be avoided when removing amino-protecting groupsand hydroxy-protecting groups, discussed below.) Preferred carboxylicacid protecting groups are the allyl and p-nitrobenzyl groups. Similarcarboxy-protecting groups used in the cephalosporin, penicillin andpeptide arts can also be used to protect a carboxy group substituents.Further examples of these groups are found in E. Haslam, “ProtectiveGroups in Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, NewYork, N.Y., 1973, Chapter 5, and T. W. Greene, “Protective Groups inOrganic Synthesis”, John Wiley and Sons, New York, N.Y., 1981, Chapter5. The term “protected carboxy” refers to a carboxy group substitutedwith one of the above carboxy-protecting groups.

As used herein the term “amide-protecting group” refers to any grouptypically used in the peptide art for protecting the peptide nitrogensfrom undesirable side reactions. Such groups include p-methoxyphenyl,3,4-dimethoxybenzyl, benzyl, O-nitrobenzyl, di-(p-methoxyphenyl)methyl,triphenylmethyl, (p-methoxyphenyl)diphenylmethyl,diphenyl-4-pyridylmethyl, m-2-(picolyl)-N′-oxide, 5-dibenzosuberyl,trimethylsilyl, t-butyl dimethylsilyl, and the like. Furtherdescriptions of these protecting groups can be found in “ProtectiveGroups in Organic Synthesis”, by Theodora W. Greene, 1981, John Wileyand Sons, New York.

The terms “heterocyclic group”, “heterocyclic”, “heterocyclyl”, or“heterocyclo” alone and when used as a moiety in a complex group such asa heterocycloalkyl group, are used interchangeably and refer to anymono-, bi-, or tricyclic saturated or non-aromatically unsaturated ringhaving the number of atoms designated, generally from 3 to about 10 ringatoms, where the ring atoms are carbon and 1,2,3 or 4 nitrogen, sulfuror oxygen atoms. Typically, a 5-membered ring has 0 to 2 double bondsand 6- or 7-membered ring has 0 to 3 double bonds and the nitrogen orsulfur heteroatoms may optionally be oxidized, and any nitrogenheteroatom may optionally be quatemized. Examples include pyrrolidinyl,oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl,tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl,aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperidinyl, and3,4,5,6-tetrahydropiperidinyl.

A “heterocycloalkyl” or a “heterocycloalkenyl” group is a heterocyclogroup as defined above covalently bonded to an alkyl or alkenyl group asdefined above.

Unless otherwise specified, “heteroaryl” alone and when used as a moietyin a complex group such as a heteroaralkyl group, refers to any mono-,bi-, or tricyclic aromatic ring system having the number of atomsdesignated where at least one ring is a 5-, 6- or 7-membered ringcontaining from one to four heteroatoms selected from the groupnitrogen, oxygen, and sulfur,and preferably at least one heteroatom isnitrogen (Lang's Handbook of Chemistry, supra). Included in thedefinition are any bicyclic groups where any of the above heteroarylrings are fused to a benzene ring. Heteroaryls in which nitrogen oroxygen is the heteroatom are preferred.

The following ring systems are examples of the heteroaryl (whethersubstituted or unsubstituted) groups denoted by the term “heteroaryl”:thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl,thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl,dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl,dithiadiazinyl, imidazolinyl, dihydropyritnidyl, tetrahydropyrimidyl,tetrazolo[1,5-b]pyridazinyl and purinyl, as well as benzo-fusedderivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl,benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.

Heterocyclic 5-membered ring systems containing a sulfur or oxygen atomand one to three nitrogen atoms are also suitable for use in the instantinvention. Examples of such preferred groups include thiazolyl, inparticular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, inparticular 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl,preferably oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl,and 1,2,4-oxadiazol-5-yl. A group of further preferred examples of5-membered ring systems with 2 to 4 nitrogen atoms include imidazolyl,preferably imidazol-2-yl; triazolyl, preferably 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, preferably1H-tetrazol-5-yl. A preferred group of examples of benzo-fusedderivatives are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.

Further suitable specific examples of the above heterocylic ring systemsare 6-membered ring systems containing one to three nitrogen atoms. Suchexamples include pyridyl, such as pyrid-2-yl, pyrid-3-yl, andpyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl;triazinyl, preferably 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl;pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridineN-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl,pyrimid4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are apreferred group.

The substituents for the optionally substituted heterocyclic ringsystems, and further examples of the 5- and 6-membered ring systemsdiscussed above can be found in W. Druckheimer et al., U.S. Pat. No.4,278,793.

A particularly preferred group of “heteroaryl” include;1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl,2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-ylsodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl,1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl,2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl 1,2,4-oxadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl,2-(methylthio)-1,3,4-thiadizol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl,1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-ylsodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl sodium salt, 2-methyl-1H-tetrazol-5-yl,1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-ylN-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl,1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-as-triazin-3-yl,2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl and8-aminotetrazolo[1,5-b]-pyridazin-6-yl.

An alternative group of “heteroaryl” includes;4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl,1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-ylsodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl sodium salt, 1,2,3-triazol-5-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl, and8-aminotetrazolo[1,5-b]pyridazin-6-yl.

A “heteroaralkyl” or a “heteroaralkenyl” group is a heteroaryl group asdefined above covalently bonded to an alkyl group or to an alkenyl groupas defined above.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. “Pharmaceutically acceptable acid addition salt” refers to thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

“Pharnaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,bydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic non-toxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

The term “prodrug” as used herein means a derivative of a parent drugmolecule that enhances pharmaceutically desirable characteristics orproperties (e.g. transport, bioavailablity, pharmacodynamics, etc.) andthat requires biotransformation, either spontaneous or enzymatic, withinthe organism to release the active parent drug.

EMBODIMENTS

The invention is generally directed to compounds having the structureshown below.

In this structure R₇, R₅, R₆, A, B, N1, N2, Q, X, and Y have themeanings described above. In these meanings, alkyl is preferablyunsubstituted or substituted C₁-C₆ alkyl; alkenyl is preferablyunsubstituted or substituted C₂-C₆ alkenyl; alkynyl is preferablyunsubstituted or substituted C₂-C₆ alkynyl; aryl is preferablyunsubstituted or substituted naphthyl or phenyl, more preferably phenyl;aralkyl is preferably unsubstituted or substituted benzyl. The variablem is preferably 1.

The group Y is preferably S(O)_(n)—R₁ where n=1 or 2 or the groupS(O)_(n)—NR₂R₂ where n=1 or 2, more preferably S(O)_(n)—R₁.

In one preferred embodiment, R₁, for example when Y is S(O)_(n)—R₁, isselected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl; C₂-C₆alkynyl, C₃-C₆ cycloalkyl, phenyl, naphthyl, benzyl and heteroarylhaving 5-6 ring atoms selected from carbon atoms and 1-2 heteroatoms,where the heteroatoms are N, S, or O, and R₁ optionally substituted with1-3 substituents selected from the group consisting of halo, nitro,C₁-C₆ alkyl, NR₇R₈, OR₇, SR₇, C₁-C₆ alkyl-C(O)OR₇, C₁-C₆ alkyl-OC(O)R₇,C₁-C₆alkyl-C(O)R₇, C₁-C₆ alkyl-OR₇, C₁-C₆ haloalkyl, C₁-C₆ alkyl-NR₇R₈,C(O)OR₇, OC(O)R₇, C(O)NR₇R₈, OC(O)NR₇R₈, NHC(O)R₇, and NHC(O)NR₇R₈,where R₇ and R₈ independently are H or C₁-C₆ alkyl. In this embodiment,each of the remaining variables R₂, R₅, R₆, A, B, Q, X, and Y may beindependently selected to be any of the groups in the respectivedefinitions described above.

In a second preferred embodiment, Q is phenyl optionally substitutedwith 1-5, preferably 2-4, more preferably 2-3, substituents selectedfrom the group consisting of halo, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, NR₇R₈, OR₇, SR₇, C₁-C₆ alkyl-C(O)OR₇, OC₁-C₆alkyl-C(O)OR₇, C₁-C₆ alkyl-OR₇, OC₁-C₆ alkyl-OR₇, C₁-C₆ alkyl-NR₇R₈,OC₁-C₆ alkyl-NR₇R₈, C₁-C₆ alkyl-C(O)NR₇R₈, OC₁-C₆ alkyl-C(O)NR₇R₈, C₁-C₆alkyl-C(O)R₇, OC₁-C₆ alkyl-C(O)R₇, C₁-C₆ haloalkyl, O-aralkyl (e.g.benzoxy), C(O)OR₇, C(O)NR₇R₈, OC(O)NR₇R₈, NHC(O)R₇, NHC(O)NR₇R₈,NR₇S(O)_(n)R₁, NR₇S(O)_(n)R₇,S(O)_(n)R₇, S(O)_(n)NR₇, where R₇ and R₈independently are H or C₁-C₆ alkyl. In this embodiment, each of theremaining variables R₂, R₅, R₆, A, B, X, and Y (and R₁) may beindependently selected to have any of the definitions described above.Each alkyl, alkenyl and alkynyl moiety may also be substituted asdefined above.

In a third preferred embodiment, Q has the structure

where

R₉ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,hydroxy, NR₇R₈, SR₇ or OR₇, where R₇ and R₈, independently, are H orunsubstituted or substituted C₁-C₆ alkyl;

R₁₀, R₁₁ and Z₂, independently, are each selected from the groupconsisting of H, halo, nitro, cyano, C₁-C₆ alkyl, C₆-C₁₀ aryl, NR₇R₈,OR₇, SR₇, C₁-C₆ alkyl-C(O)R₇, C₁-C₆ alkyl-C(O)NR₇R₈, C₁-C₆alkyl-C(O)OR₇, C₁-C₆ alkyl-OC(O)R₇, C₁-C₆ alkyl-OR₇, OC₁-C₆alkyl-C(O)R₇, OC₁-C₆ alkyl-C(O)OR₇, OC₁-C₆ alkyl-OC(O)R₇, O—C₁-C₆alkyl-OR₇, OC₁-C₆ alkyl-C(O)NR₇R₈, C₁-C₆ haloalkyl, OR₁₂, C₁-C₆alkyl-R₁₂, O—C₁-C₆ alkyl-R₁₂, C(O)OR₇, C(O)OR₁₂, C(O)NR₇R₈, OC(O)NR₇R₈,NR₇C(O)R₇, NR₇C(O)R₁₂, NR₇C(O)—NR₇R₈, NR₇C(O)OR₇, NR₇C(O)OR₁₂,NR₇S(O)n—R₁, NR₇S(O)n—R₇ and NR₇S(O)n—R₁₂, where R₇ and R₈,independently, are H or unsubstituted or substituted C₁-C₆ alkyl, R₁₂ isunsubstituted or substituted C₆-C₁₀ aryl or heterocycl as defined aboveand n is 1 or 2;

Z₁ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen or nitro. In thisembodiment, each of the remaining variables R₂, R₅, R₆, A, B, X, and Ymay be independently selected to have any of the definitions describedabove. Each alkyl, alkenyl and alkynyl moiety may also be substituted asdefined above.

In various aspects of the invention, Z₁ and Z₂ may be hydrogen; Z₁, Z₂and R₁₁ may be hydrogen; or Z₁, R₁₀ and R₁₁ may be hydrogen; and theremaining ring substituents are as defined above.

In another embodiment, the substituents at the 4- and 5-positions or atthe 5- and 6-positions of the ring when Q is substituted phenyl may bebonded together to form an unsubstituted or substituted carbocyclic orhetercyclic ring. Examples of such compounds are shown below, where thesymbol

is preferably a 5-membered or a 6-membered carbocyclic or heterocyclicring which is fused to the phenyl ring in the positions shown below.

Examples of suitable 5-membered or a 6-membered carbocyclic orheterocyclic rings which may be fused to the phenyl ring include thering systens shown below, where R₆ is as defined above.

In another preferred embodiment, Y is S(O)_(n)—R₁ where n is 1 or 2,preferably 2. In this embodiment, R₁ may be as defined above and each ofthe remaining variables may be independently selected to have any of thedefinitions described above.

Compounds in which Q is substituted phenyl and R₁₀ is selected from thegroup consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ aminoalkyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, phenyl, phenoxy, benzyl, benzyloxy, aswell as phenoxy- and benzyloxy-substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl,OC(O)-C₁-C₆ alkyl, C(O)O—C₁-C₆ alkyl and C(O)OH are also preferred,where each of the remaining variables may be independently selected tohave any of the definitions described above.

Also of interest are compounds in which R₁₁ is NR₇C₁-C₆ alkyl-C(O)NR₇R₈,NR₇S(O)n—R₇ or N R₇S(O)n—R₁₂, n is 1 or 2 and/or where Z₁=Z₂=H and/orwhere R₁₀ is OR₇, OR₁₂, OC₇-C₁₀-aralkyl, OC₁-C₆ alkyl-OR₇ or OC₁-C₆alkyl-OR₁₂ where R₇ and R₁₂ are unsubstituted or substituted as definedabove. Suitable substituted R₇ and R₁₂ include these groups substitutedas described above, for example, having 1 or 2 C₁-C₆ alkoxy, C₁-C₆alkoxy-C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆aminoalkyl, OC(O)-C₁-C₆ alkyl, C(O)O—C₁-C₆ alkyl, C₁-C₆ alkyl C(O)OR₇,C₁-C₆ alkyl OC(O)R₇ or C(O)OH. In these compounds, each of the remainingvariables may be independently selected to have any of the definitionsdescribed above. These compounds are also interesting where, Y isS(O)_(n)—R₁ where n is 1 or 2, that is, disulfonamide comounds.

In another embodiment, A and B are independently CH or CR₃, where R₃ isH, C₁-C₆ alkyl or OH, where the remaining variables may be independentlyselected to have any of the definitions described above.

In another embodiment, R₆ is H or R₃ is CH, where the remainingvariables may be independently selected to have any of the definitionsdescribed above.

In another preferred embodiment, X is a carbonyl group (C═O), where theremaining variables may be independently selected to have any of thedefinitions described above. In this embodiment, preferably m=1.

Table 1, setting forth examples of some preferred groups at variouspositions of some compounds of the invention, is shown below. A group ofspecific compounds is disclosed in this table and is obtained byselecting all unique combinations of substituents, one from each columnof the table, for each variable and combining these groups with thestructure disclosed above Table 1.

TABLE 1

X R9 R10 Z2 R11 R1 Z3 CH2 OEt OEt H H Me H C═O OMe OH OEt NMeSO2Me Et OHCH2CH3 OMe OMe Ph Pr Cl CH═CH2 OiPr Ph Naphthyl Bu F CCH OCH2Ph OiPr iPrCH2CCH CH(CH3)Ph OPr NHSO2Me iBu H CH(CH2Cl)Ph CH(CH2Cl)Ph NPrSO2Me sBuPr OCH2CH2CF3 OCH2CH2CF3 N(CH2CO2H)SO2Me Ph Cl OCH2CF3 OCH2CF3NMeSO2CH2CO2H O-tolyl SCH3 CH(CO2H)Ph CH(CO2H)Ph NHSO2CH2CO2H CH2CH2CO2HSCH2CH3 CH(CO2Me)Ph CH(CO2Me)Ph NHCOCH3 CH2CH2CONH2 NHCH3 Ph PhNHCOCH2CO2H CH2CH2CO2Me NHCH2CH3 OPh OPh NHSO2-thiophene p-tolyl H ClNHSO2CH2CO2H 4-chlorophenyl Cl Br NHSO2CH2CO2Me 4-aminomethylphenyl Br FOCH2CO2H 4-aminophenyl F OCH2Ph pyridyl 2-chlorophenyl H NCH2CH33-nitrophenyl NHCH2CH3 SCH3 1-naphthyl 2-thiophene 3-thiophene 2-furan3-furan CH2CH(NH2)CH3 pyridyl 2-naphthyl

METHODS OF MAKING

Compounds of the present invention can be prepared by methods employingstandard chemical methodologies described and referenced in standardtextbooks (e.g. March, J. “Advanced Organic Chemistry” McGraw-Hill, NewYork, 1977; Collman, J. P., Hegedus, L. S., Norton, J. R., Finke, R. G.“Principles and Applications of Organotransition Metal Chemistry”University Science, Mill Valley, 1987; Larock, R. C. “ComprehensiveOrganic Transformations” Verlag, New York, 1989).

A key intermediate in the synthesis of compounds of the invention hasthe formula shown below

In this formula, A, B, R₂, R_(4a), R_(4b), R₅, R₆, m and Q have themeanings and preferred meanings described above. This compound can beprepared using several alternative synthetic routes. After preparation,the cyano group may be converted into an amidino group (C(NH)NH₂), forexample, using known procedures, such as the Pinner reaction. A cyanocompound having the formula shown above may be reacted with hydroxylamine, preferably in an alcohol solvent, followed by reduction withRaney Ni, preferably in an alcohol solvent, or may be reacted first withethanolic HCl and then with alcoholic ammonia to yield the correspondingamidino compounds. Alternatively, a modified Pinner reaction usingpyridine/diethylamine (1/1)/hydrogen sulfide followed by methyliodide/acetonitrile and then ammonium acetate/ethanol will provide thedesired amidino product.

One synthetic route to compounds having the formula shown above is acondensation reaction using appropriately substituted precursors asshown in the scheme below.

This condensation is performed in the presence of a catalyst, preferablya Lewis acid catalyst, and an alkyl alcohol (ROH), preferably a loweralkyl alcohol such as methanol, ethanol, i-propanol, etc., followed byhydrolysis of the intermediate, preferably with an excess of water,generally up to about 10 equivalents of water. Suitable Lewis Acidsinclude BF₃ etherate, AlCl₃, etc. W—NC is an isonitrile in which W maybe any suitable hydrocarbon group, generally an alkyl, carbocycloalkyl,or aralkyl group, preferably having no more than about 12 carbon atoms.A particularly preferred isonitrile is benzyl isonitrile. The esterproduct may be purified by standard techniques, including high pressureliquid chromatography (HPLC), column chromatography, recrystallization,etc.

Reduction of the resulting ester to an alcohol can be accomplished usingany known reducing agent ([H]) which will preferentially reduce an esterbefore a nitrile. Suitable reducing agents and procedures are well knownin the art. See, for example, Modern Synthetic Reactions, H. O. House,W. A. Benjami, Inc., Second Ed., 1972. A useful reducing agent islithium borohydride. The alcohol may then be converted to an amine usingknown chemical reactions. Suitable conditions include first reacting thealcohol with hydrogen azide, DEAD, and triphenyl phosphine (PPh₃),following by PPh₃ and water or first with phthalimide, DEAD and PPh₃,followed by hydrazine. These reactions are shown in the scheme below.Alternatively, the ester may be reacted with a reagent having anucleophilic carbon atom to introduce suitable R_(4a) groups. Suchreagents may include an activated methylene carbon, for example amethylene which is adjacent to one or more strong electron withdrawinggroups such as nitro (NO₂), carboalkoxy (COOR_(4a)), etc., Grignardreagents (R_(4a)MgHal, where Hal is a halogen), etc. and then convertedto the alcohol and to the amine.

Conversion of the amine functional group to a sulfonamide and theconversion of the nitrile functional group to an amidine may beperformed in any desired order. A preferred reaction scheme is shown inthe scheme below.

These conversions are accomplished using known chemical reactions,purification and separation procedures. The amine may be converted to asulfonamide by reaction with an appropriately substituted sulfonylchloride (ClSO₂R₁) in the presence of a base. The nitrile may be reactedwith hydroxyl amine in an alcohol solvent followed by reduction, forexample, with Raney nickel and hydrogen, or by reaction with HCl/alcoholand then ammonia/alcohol.

An example of a suitable reaction sequence is shown below.

In this sequence, a=BF₃OEt₂/EtOH, b=LiBH₄/DME,c=phthalimide,DIAD/PPh₃/THF, d=H₂NNH₂/EtOH, e=R₁SO₂Cl, f=H₂/Pt/C/EtOH,and g=R₇SO₂Cl/NEt₃, NH₂OH-HCl/NEt₃, H₂/Ra—Ni/MeOH.

An analogous related synthetic scheme may be used to prepare thecorresponding compounds in which X is a carbonyl as shown below.

Compounds in which m=2 can be prepared using according to the schemeshown below which provides an alcohol which is homologous to the alcoholshown in the scheme above and which can be converted to an amine (andfurther elaborated compounds) in an analogous manner. In the schemebelow, (a) is a base and (b) is a reducing agent such as LiBH₄

Compounds in which Y is C(O)—R₁; C(O)—OR¹; C(O)—NR¹R₂ are prepared asdescribed above using the corresponding acyl halide (preferably an acylchloride), alkyl haloforrnate (preferably a chloroformate) or isocyanateas shown in the scheme below:

An example of a suitable reaction sequence is shown below.

The esters resulting from the condensation reactions shown above canalso function as intermediates in the synthesis of compounds in which Xis a carbonyl group. Conversion of the ester to a carboxylic acid iseasily performed by saponification with an alkali-metal hydroxide suchas lithium, sodium, or potassium hydroxide. Coupling of a sulfonamide tothe acid is accomplished by first activating the carboxylate forcoupling using, for example, carbonyl diimidazole or other routineactivating agents used in peptide synthesis. The second part of thecoupling is done by mixing an alkyl or aryl sulfonamide with a strongbase such as DBU or sodium hydride, preferably in an anhydrous solvent,such as a hydrocarbon or ether solvent, e.g. tetrahydrofuran. Thenitrile is converted to an amidine by methods already described.

In a more preferred variation of this embodiment, Q is a substitutedphenyl having substituents Z₁, Z₂, and R₉-R₁₁ as described below.

A further method of preparing intermediate compounds useful in preparingthe compounds of the invention is shown below and involves the synthesisof imine compounds from readily available aldehydes and ketones followedby nucleophilic addition of a nucleophilic carbon atom containingreagent, i.e. in general “Nu⁻”. “Nu” may be a moiety such asCHR_(4a)NO₂, CHR_(4a)COOR, CH(NO₂)(COOR), etc., which are generatedusing well known Grignard reactions, reactions in which a base is usedto remove a proton from the carbon atom adjacent to an electronwithdrawing group (CO, COO, NO₂), etc.

“Nu” can be converted into a group such as CHR_(4a)NH₂ or CHR_(4a)CH₂OHor CHR_(4a)NH₂CH₂OH by known reduction reactions as shown below. Inthese intermediates, an amino group can be further sulfonated orotherwise acylated as described above. An example of a suitable reactionsequence is shown below.

An alternative synthetic procedure can be used to prepare the alcoholintermediates described above. As shown in the scheme below, reaction ofan initial styrene derivative with a peracid usually produces a mixtureof products containing non-hydrogen R_(4a) and/or R₅ substituents asshown below which can be converted without separation to the alcohol byreaction with a cyano-aniline or corresponding cyano-pyridine.

The alcohol can then be used to prepare compounds of the invention asdescribed above.

When the corresponding compounds in which A and B are nitrogen aredesired, the aniline or substituted aniline used in the reactionsdescribed above is replaced with the corresponding amino-pyridine orsubstituted amino-pyridine compounds.

Compounds in which the sulfonamide nitrogen bears a substituent can beprepared by conventional alkylation of the nitrogen atom using knownreactions, for example, alkylation with dialkyl sulfate, alkyl halideetc, according to known procedures.

In a preferred embodiment, Q is a substituted aryl, and more preferably,a substituted phenyl group and has the structure shown below.

In this structure, Z₁, Z₂, R₉-R₁₁ are as defined above both generallyand in preferred embodiments. Compounds of this embodiment are preparedas described in scheme 1 above using an appropriately substitutedbenzaldehyde having structure Q—CHO (R₅ is H). These substitutedbenzaldehydes are readily available from commercial sources or can beeasily prepared from known benzaldehydes using well known syntheticchemistry.

In one embodiment, Q is substituted with a nitro group. A preferredposition for the nitro group is at R₁₁ (where Z₁, Z₂, R₉ and R₁₀ are asdefined above generally and in preferred embodiments), which nitro groupcan be further reduced to an amino group using a suitable reducingagent. Generally, the cyano-amine compound or the cyano-sulfonamidecompound shown in scheme 3 will be reacted with a reducing agent whichwill preferentially reduce the nitro group at R₁₁ over the cyano group.Any reducing agent having these properties may be used, for example,hydrogen and a Pt/C catalyst. The aniline resulting from the reductioncan then be reacted with a sulfonyl chloride (ClSO₂W where W is asdefined above) to produce a disulfonamide compound.

The preparation of cyclic urea derivatives in which N₁—R₂ and N₂—R₂together form a urea linkage, i.e. N₁—C(O)—N₂, provides additionalcompounds of the invention and provides an additional method ofpreparing enentiomerically pure compounds of the invention. The cyclicurea compounds can be used, for example, to prepare dialkoxybis-sulfonamides and other compounds of the invention as shown in thescheme below.

Alternatively, nitric acid can be replaced by sulfuric acid in thescheme below to give sulfonic acid derivatives which can be furtherconverted to sulfonamides and sulfones by known reactions.

Other compounds of the invention, including heterocyclic compounds, arereadily prepared from simple starting materials which can be used in thesynthetic schemes described above. For example, beginning with simplenitro and hydroxy substituted aldehydes, condensation as described aboveprovides the corresponding esters which can be converted directly tocyclic urethane or oxazole compounds which can then be furtherelaborated as already described to provide compounds of the invention.These reactions are shown schematically below for rings fused in the5-position and 6-position.

Compounds in which the ring is fused to the 4-position and the5-position of the phenyl ring are prepared by analogous methods statingwith the appropriately substituted aldehyde as shown below.

Other fused heterocyclic compounds are prepared using conventionalsynthetic chemical reactions and appropriately substituted startingmaterials which are well known in the art of chemical synthesis toprovide additional compounds of the invention. For example, fused furanring systems can be prepared from the corresponding halo and hydroxysubstituted aldehydes as shown below.

Also included in the scope of this invention are prodrugs of thecompounds described above. Suitable prodrugs include knownamino-protecting and carboxy-protecting groups which are released, forexample hydrolyzed, to yield the parent compound under physiologicconditions. A preferred class of prodrugs are compounds in which anitrogen atom in an amino, amidino, aminoalkyleneamino,iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH)group, an alkylcarbonyl (—CO—W) group, an alkoxycarbonyl (—CO—OW), anacyloxyalkyl-alkoxycarbonyl (—CO—O—W—O—CO—W) group where W is amonovalent or divalent group and as defined above or a group having theformula —C(O)—O—CP1P2-haloalkyl, where P1 and P2 are the same ordifferent and are H, lower alkyl, lower alkoxy, cyano, halo lower alkylor aryl. Preferably the nitrogen atom is one of the nitrogen atoms ofthe amidino group of the compounds of the invention. These prodrugcompounds are prepared reacting the compounds of the invention describedabove with an activated acyl compound to bond a nitrogen atom in thecompound of the invention to the carbonyl of the activated acylcompound. Suitable activated carbonyl compounds contain a good leavinggroup bonded to the carbonyl carbon and include acyl halides, acylamnines, acyl pyridinium salts, acyl alkoxides, in particular acylphenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl,fluorophenoxy acyl, and defluorophenoxy acyl. The reactions aregenerally exothermic and are carried out in inert solvents at reducedtemperatures such as −78 to about 50 C. The reactions are usually alsocarried out in the presence of an inorganic base such as potassiumcarbonate or sodium bicarbonate, or an organic base such as an amine,including pyridine, triethylamine, etc. One manner of preparing prodrugsis described in WO98/46576, published Oct. 22, 1998.

Using the synthetic methods described above, the following exemplarycompounds of the invention shown in Table 2 below can be prepared (m=1).For each entry in the table, X may be carbonyl or (CR_(4a)R_(4b))_(m)where m=1 or 2; and the benzamidine ring may bear a halogen, hydroxy oralkyl substituent.

TABLE 2

Compound No. Z² R¹ R⁹ R¹⁰ R¹¹  1 —H

OCH₃

H  2 —H

OCH₃

H  3 —H

OCH₃

H  4 —H

OCH₃

H  5 —H

OCH₃

H  6 —H

OCH₃

H  7 —H

OCH₃

H  8 —H

OCH₃

H  9 —H

OCH₃

 10 —H

OCH₃ OCH₃ Br  11 —H

OCH₃

H  12 —H —CH(CH₃)₂ OCH₃

H  13 —H —CH₂CH₂CH₃ OCH₃

CH₃SO₂—NH  14 —H

OCH₃

H  15 —H

OCH₃

H  16 —H

OCH₃

H  17 —H —CH₂CH₃ OCH₃

H  18 —H

OCH₃

H  19 —H

OCH₃

H  20 —H

OCH₃

H  21 —H

OCH₃

H  22 —H

OCH₃

H  23 —H

OCH₃

H  24 —H —CH₃ OCH₃

H  25 —H

OCH₃

H  26 —H

OCH₃

H  27 —H

OCH₃

H  28 —H

OCH₃

H  29 —H

OCH₃

H  30 —H

OCH₃

H  31 —H

OCH₃

H  32 —H

OCH₃

H  33 —H —CH₂CH₂CH₃ OCH₃

H  34 —H —CH₂CH₂CH₂CH₃ OCH₃

H  35 —H

OCH₃

H  36 —H

OCH₃

H  37 —H —CH₂CH₂CH₃ OCH₃

H  38 —H —CH₂CO₂CH₂CH₃ OCH₃

H  39 —H —CH₂CO₂H OCH₃

H  40 —H —(CH₂)₆CH₃ OCH₃

H  41 —H —CH═CH₂ OCH₃

H  42 —H —CH₂—C≡CH OCH₃

H  43 —H

OCH₃

H  44 —H

OCH₃

H  45 —H

OCH₃

H  46 —H

OCH₃

H  47 —H

OCH₃

H  48 —H

OCH₃

H  49 —H

OCH₃

H  50 —H

OCH₃

H  51 —H

OCH₃

H  52 —H

OCH₃

H  53 —H

OCH₃

H  54 —H

OCH₃

H  55 —H

OCH₃

H  56 —H

OCH₃

H  57 —H

OCH₃

H  58 —H

OCH₃

H  59 —H

OCH₃

H  60 —H

OCH₂CH₃ OCH₂CH₃ H  61 —H

OCH₂CH₂CH₃

H  62 —H

OCH₂CH₂CH₃

H  63 —H

OCH₂CH₃

H  64 —H

OCH₂CH₃

H  65 —H

OCH₂CH₃

H  66 —H

OCH₂(CH₂)₄CH₃

H  67 —H

OCH₂CH₃

H  68 —H

OCH₂CH₃

 69 —H

OCH₂CH₃ OCH₃ Br  70 —H

OCH₂CH₃

H  71 —H —CH(CH₃)₂ OCH₂CH₃

H  72 —H —CH₂CH₂CH₃ OCH₂CH₃

CH₃SO₂—NH  73 —H

OCH₂CH₃

H  74 H —CH₂CH₂CH₃ OCH₂CH₃

CH₃CH₂—O₂CCH₂SO₂NH—  75 —H —CH₂CH₂CH₃ OCH₂CH₃

HO₂CCH₂SO₂NH—  76 —H —CH₂CH₂CH₃ OCH₂CH₃

 77 —H —CH₂CH₂CH₃ OCH₂CH₃

 78 —H

OCH₂CH₃

H  79 —H

OCH₂CH₃

H  80 —H —CH₂CH₃ OCH₂CH₃

H  81 —H

OCH₂CH₃

H  82 —H

OCH₂CH₃

H  83 —H

OCH₂CH₃

H  84 —H

OCH₂CH₃

H  85 —H

OCH₂CH₃

H  86 —H

OCH₂CH₃

H  87 —H —CH₃ OCH₂CH₃

H  88 —H

OCH₂CH₃

H  89 —H

OCH₂CH₃

H  90 —H

OCH₂CH₃

H  91 —H

OCH₂CH₃

H  92 —H

OCH₂CH₃

H  93 —H

OCH₂CH₃

H  94 —H

OCH₂CH₃

H  95 —H

OCH₂CH₃

H  96 —H —CH₂CH₂CH₃ OCH₂CH₃

H  97 —H —CH₂CH₂CH₂CH₃ OCH₂CH₃

H  98 —H

OCH₂CH₃

H  99 —H

OCH₂CH₃

H 100 —H —CH₂CH₂CH₃ OCH₂CH₃

H 101 —H —(CH₂)₆CH₃ OCH₂CH₃

H 102 —H —CH═CH₂ OCH₂CH₃

H 103 —H —CH₂—C≡CH OCH₂CH₃

H 104 —H

OCH₂CH₃

H 105 —H

OCH₂CH₃

H 106 —H

OCH₂CH₃

H 107 —H

OCH₂CH₃

H 108 —H

OCH₂CH₃

H 109 —H

OCH₂CH₃

H 110 —H

OCH₂CH₃

H 111 —H

OCH₂CH₃

H 112 —H

OCH₂CH₃

H 113 —H

OCH₂CH₃

H 114 —H

OCH₂CH₃

H 115 —H

OCH₂CH₃

H 116 —H

OCH₂CH₃

H 117 —H

OCH₂CH₃

H 118 —H

OCH₂CH₃

H 119 —H

OCH₂CH₃

H 120 —H

OCH₂CH₃

H 121 —H

OH

H 122 —H

OH

H 123 —H

OH

H 124 —H

OH

H 125 —H

OH

H 126 —H

OH

H 127 —H

OH

H 128 —H

OH

129 —H

OH OCH₃ Br 130 —H

OH

H 131 —H —CH(CH₃)₂ OH

H 132 —H —CH₂CH₂CH₃ OH

CH₃SO₂—NH— 133 —H

OH

H 134 —H

OH

H 135 —H

OH

H 136 —H —CH₂CH₃ OH

H 137 —H

OH

H 138 —H

OH

H 139 —H

OH

H 140 —H

OH

H 141 —H

OH

H 142 —H

OH

H 143 —H —CH₃ OH

H 144 —H

OH

H 145 —H

OH

H 146 —H

OH

H 147 —H

OH

H 148 —H

OH

H 149 —H

OH

H 150 —H

OH

H 151 —H

OH

H 152 —H —CH₂CH₂CH₃ OH

H 153 —H —CH₂CH₂CH₂CH₃ OH

H 154 —H

OH

H 155 —H

OH

H 156 —H —CH₂CH₂CH₃ OH

H 157 —H —(CH₂)₆CH₃ OH

H 158 —H —CH═CH₂ OH

H 159 —H —CH₂—C≡CH OH

H 160 —H

OH

H 161 —H

OH

H 162 —H

OH

H 163 —H

OH

H 164 —H

OH

H 165 —H

OH

H 166 —H

OH

H 167 —H

OH

H 168 —H

OH

H 169 —H

OH

H 170 —H

OH

H 171 —H

OH

H 172 —H

OH

H 173 —H

OH

H 174 —H

OH

H 175 —H

OH

H 176 —H

OH

H 177 —H

—CH₃

H 178 —H

—CH₂CH₃

H 179 —H

—CH₂CH₃

H 180 —H

—CH₂CH₃

H 181 —H

—CH₂CH₂CH₃

H 182 —H

—CH₃

H 183 —H

—CH(CH₃)₂

H 184 —H

—CH₃

H 185 —H

—CH₂(CH₂)₃CH₃

186 —H

—CH₃ OCH₃ Br 187 —H

—CH₃

H 188 —H —CH(CH₃)₂ —CH₃

H 189 —H —CH₂CH₂CH₃ —CH₃

CH₃SO₂—NH— 190 —H

—CH₃

H 191 —H

—CH₃

H 192 —H

—CH₃

H 193 —H —CH₂CH₃ —CH₃

H 194 —H

—CH₃

H 195 —H

—CH₃

H 196 —H

—CH₃

H 197 —H

—CH₃

H 198 —H

—CH₃

H 199 —H

—CH₃

H 200 —H —CH₃ —CH₃

H 201 —H

—CH₃

H 202 —H

—CH₃

H 203 —H

—CH₃

H 204 —H

—CH₃

H 205 —H

—CH₃

H 206 —H

—CH₃

H 207 —H

—CH₃

H 208 —H

—CH₃

H 209 —H —CH₂CH₂CH₃ —CH₃

H 210 —H —CH₂CH₂CH₂CH₃ —CH₃

H 211 —H

—CH₃

H 212 —H

—CH₃

H 213 —H —CH₂CH₂CH₃ —CH₃

H 214 —H —(CH₂)₆CH₃ —CH₃

H 215 —H —CH═CH₂ —CH₃

H 216 —H —CH₂—C≡CH —CH₃

H 217 —H

—CH₃

H 218 —H

—CH₃

H 219 —H

—CH₃

H 220 —H

—CH₃

H 221 —H

—CH₃

H 222 —H

—CH₃

H 223 —H

—CH₃

H 224 —H

—CH₃

H 225 —H

—CH₃

H 226 —H

—CH₃

H 227 —H

—CH₃

H 228 —H

—CH₃

H 229 —H

—CH₃

H 230 —H

—CH₃

H 231 —H

—CH₃

H 232 —H

—CH₃

H 233 —H

—CH₃

H 234 —H

—CH═CH₂

H 235 —H

—CH═CH₂

H 236 —H

—CH═CH₂

H 237 —H

—CH═CH₂

H 238 —H

—CH═CH₂

H 239 —H

—CH═CHCH₃

H 240 —H

—CH═CH₂

H 241 —H

—CH═CH₂

H 242 —H

—CH═CH₂

243 —H

—CH═CH₂ OCH₃ Br 244 —H

—CH═CH₂

H 245 —H —CH(CH₃)₂ —CH═CHCH₂CH₃

H 246 —H —CH₂CH₂CH₃ —CH═CH₂

CH₃SO₂—NH— 247 —H

—CH═CH₂

H 248 —H

—CH═CH₂

H 249 —H

—CH═CH₂

H 250 —H —CH₂CH₃ —CH═CH₂

H 251 —H

—CH═CH₂

H 252 —H

—CH₂CH═CH₂

H 253 —H

—CH═CH₂

H 254 —H

—CH═CH₂

H 255 —H

—CH═CH₂

H 256 —H

—CH═CH₂

H 257 —H —CH₃ —CH₂CH═CH₂

H 258 —H

—CH═CH₂

H 259 —H

—CH═CH₂

H 260 —H

—CH═CH₂

H 261 —H

—CH═CH₂

H 262 —H

—CH═CH₂

H 263 —H

—CH═CH₂

H 264 —H

—CH═CH₂

H 265 —H —CH₂CH₂CH₃ —CH═CH₂

H 266 —H —CH₂CH₂CH₂CH₃ —CH═CH₂

H 267 —H

—CH═CH₂

H 268 —H

—CH═CH₂

H 269 —H —CH₂CH₂CH₃ —CH═CH₂

H 270 —H —(CH₂)₅CH₃ —CH═CH₂

H 271 —H —CH═CH₂ —CH═CH₂

H 272 —H —CH₂—C≡CH —CH═CH₂

H 273 —H

—CH═CH₂

H 274 —H

—CH═CH₂

H 275 —H

—CH═CH₂

H 276 —H

—CH═CH₂

H 277 —H

—CH═CH₂

H 278 —H

—CH═CH₂

H 279 —H

—CH═CH₂

H 280 —H

—CH═CH₂

H 281 —H

—CH═CH₂

H 282 —H

—CH═CH₂

H 283 —H

—CH═CH₂

H 284 —H

—CH═CH₂

H 285 —H

—CH═CH₂

H 286 —H

—CH═CH₂

H 287 —H

—CH═CH₂

H 288 —H

—CH═CH₂

H 289 —H

—CH₂C≡CH

H 290 —H

—CH₂C≡CH

H 291 —H

—CH₂C≡CH

H 292 —H

—CH₂C≡CH

H 293 —H

—CH₂C≡CH

H 294 —H

—CH₂C≡CH

H 295 —H

—CH₂C≡CH

H 296 —H

—CH₂C≡CH

H 297 —H

—CH₂C≡CH

298 —H

—CH₂C≡CH OCH₃ Br 299 —H

—CH₂C≡CH

H 300 —H —CH(CH₃)₂ —CH₂C≡CH

H 301 —H —CH₂CH₂CH₃ —CH₂C≡CH

CH₃SO₂—NH— 302 —H

—CH₂C≡CH

H 303 —H

—CH₂C≡CH

H 304 —H

—CH₂C≡CH

H 305 —H —CH₂CH₃ —CH₂C≡CH

H 306 —H

—CH₂C≡CH

H 307 —H

—CH₂C≡CH

H 308 —H

—CH₂C≡CH

H 309 —H

—CH₂C≡CH

H 310 —H

—CH₂C≡CH

H 311 —H

—CH₂C≡CH

H 312 —H —CH₃ —CH₂C≡CH

H 313 —H

—CH₂C≡CH

H 314 —H

—CH₂C≡CH

H 315 —H

—CH₂C≡CH

H 316 —H

—CH₂C≡CH

H 317 —H

—CH₂C≡CH

H 318 —H

—CH₂C≡CH

H 319 —H

—CH₂C≡CH

H 320 —H —CH₂CH₂CH₃ —CH₂C≡CH

H 321 —H —CH₂CH₂CH₂CH₃ —CH₂C≡CH

H 322 —H

—CH₂C≡CH

H 323 —H

—CH₂C≡CH

H 324 —H —CH₂CH₂CH₃ —CH₂C≡CH

H 325 —H —(CH₂)₆CH₃ —CH₂C≡CH

H 326 —H —CH═CH₂ —CH₂C≡CH

H 327 —H —CH₂—C≡CH —CH₂C≡CH

H 328 —H

—CH₂C≡CH

H 329 —H

—CH₂C≡CH

H 330 —H

—CH₂C≡CH

H 331 —H

—CH₂C≡CH

H 332 —H

—CH₂C≡CH

H 333 —H

—CH₂C≡CH

H 334 —H

—CH₂C≡CH

H 335 —H

—CH₂C≡CH

H 336 —H

—CH₂C≡CH

H 337 —H

—CH₂C≡CH

H 338 —H

—CH₂C≡CH

H 339 —H

—CH₂C≡CH

H 340 —H

—CH₂C≡CH

H 341 —H

—CH₂C≡CH

H 342 —H

—CH₂C≡CH

H 343 —H

—CH₂C≡CH

H 344 —H

OCH₃ OCH₃ H 345 —H

OCH₃ OCH₃ H 346 —H

OCH₃ OCH₃ H 347 —H

OCH₃ OCH₃ H 348 —H

OCH₃ OCH₃ H 349 —H

OCH₃ OCH₃ H 350 —H

OCH₃ OCH₃ H 351 —H

OCH₃ OCH₃ H 352 —H

OCH₃ OCH₃

353 —H

OCH₃ OCH₃ Br 354 —H

OCH₃ OCH₃ H 355 —H —CH(CH₃)₂ OCH₃ OCH₃ H 356 —H —CH₂CH₂CH₃ OCH₃ OCH₃CH₃SO₂—NH— 357 —H

OCH₃ OCH₃ H 358 —H

OCH₃ OCH₃ H 359 —H

OCH₃ OCH₃ H 360 —H —CH₂CH₃ OCH₃ OCH₃ H 361 —H

OCH₃ OCH₃ H 362 —H

OCH₃ OCH₃ H 363 —H

OCH₃ OCH₃ H 364 —H

OCH₃ OCH₃ H 365 —H

OCH₃ OCH₃ H 366 —H

OCH₃ OCH₃ H 367 —H —CH₃ OCH₃ OCH₃ H 368 —H

OCH₃ OCH₃ H 369 —H

OCH₃ OCH₃ H 370 —H

OCH₃ OCH₃ H 371 —H

OCH₃ OCH₃ H 372 —H

OCH₃ OCH₃ H 373 —H

OCH₃ OCH₃ H 374 —H

OCH₃ OCH₃ H 375 —H —CH₂CH₂CH₃ OCH₃ OCH₃ H 376 —H —CH₂CH₂CH₂CH₃ OCH₃ OCH₃H 377 —H

OCH₃ OCH₃ H 378 —H

OCH₃ OCH₃ H 379 —H —CH₂CH₂CH₃ OCH₃ OCH₃ H 380 —H —(CH₂)₆CH₃ OCH₃ OCH₃ H381 —H —CH═CH₂ OCH₃ OCH₃ H 382 —H —CH₂—C≡CH OCH₃ OCH₃ H 383 —H

OCH₃ OCH₃ H 384 —H

OCH₃ OCH₃ H 385 —H

OCH₃ OCH₃ H 386 —H

OCH₃ OCH₃ H 387 —H

OCH₃ OCH₃ H 388 —H

OCH₃ OCH₃ H 389 —H

OCH₃ OCH₃ H 390 —H

OCH₃ OCH₃ H 391 —H

OCH₃ OCH₃ H 392 —H

OCH₃ OCH₃ H 393 —H

OCH₃ OCH₃ H 394 —H

OCH₃ OCH₃ H 395 —H

OCH₃ OCH₃ H 396 —H

OCH₃ OCH₃ H 397 —H

OCH₃ OCH₃ H 398 —H

OCH₃ OCH₃ H 399 —H

OCH₃ OCH₂CH₃ H 400 —H

OCH₃ OCH₂CH₃ H 401 —H

OCH₃ OCH₂CH₃ H 402 —H

OCH₃ OCH₂CH₃ H 403 —H

OCH₃ OCH₂CH₃ H 404 —H

OCH₃ OCH₂CH₃ H 405 —H

OCH₃ OCH₂CH₃ H 406 —H

OCH₃ OCH₂CH₃ H 407 —H

OCH₃ OCH₂CH₃

408 —H

OCH₃ OCH₂CH₃ Br 409 —H

OCH₃ OCH₂CH₃ H 410 —H —CH(CH₃)₂ OCH₃ OCH₂CH₃ H 411 —H —CH₂CH₂CH₃ OCH₃OCH₂CH₃ CH₃SO₂—NH— 412 —H

OCH₃ OCH₂CH₃ H 413 —H

OCH₃ OCH₂CH₃ H 414 —H

OCH₃ OCH₂CH₃ H 415 —H —CH₂CH₃ OCH₃ OCH₂CH₃ H 416 —H

OCH₃ OCH₂CH₃ H 417 —H

OCH₃ OCH₂CH₃ H 418 —H

OCH₃ OCH₂CH₃ H 419 —H

OCH₃ OCH₂CH₃ H 420 —H

OCH₃ OCH₂CH₃ H 421 —H

OCH₃ OCH₂CH₃ H 422 —H —CH₃ OCH₃ OCH₂CH₃ H 423 —H

OCH₃ OCH₂CH₃ H 424 —H

OCH₃ OCH₂CH₃ H 425 —H

OCH₃ OCH₂CH₃ H 426 —H

OCH₃ OCH₂CH₃ H 427 —H

OCH₃ OCH₂CH₃ H 428 —H

OCH₃ OCH₂CH₃ H 429 —H

OCH₃ OCH₂CH₃ H 430 —H —CH₂CH₂CH₃ OCH₃ OCH₂CH₃ H 431 —H —CH₂CH₂CH₂CH₃OCH₃ OCH₂CH₃ H 432 —H

OCH₃ OCH₂CH₃ H 433 —H

OCH₃ OCH₂CH₃ H 434 —H —CH₂CH₂CH₃ OCH₃ OCH₂CH₃ H 435 —H —(CH₂)₆CH₃ OCH₃OCH₂CH₃ H 436 —H —CH═CH₂ OCH₃ OCH₂CH₃ H 437 —H —CH₂—C═CH OCH₃ OCH₂CH₃ H438 —H

OCH₃ OCH₂CH₃ H 439 —H

OCH₃ OCH₂CH₃ H 440 —H

OCH₃ OCH₂CH₃ H 441 —H

OCH₃ OCH₂CH₃ H 442 —H

OCH₃ OCH₂CH₃ H 443 —H

OCH₃ OCH₂CH₃ H 444 —H

OCH₃ OCH₂CH₃ H 445 —H

OCH₃ OCH₂CH₃ H 446 —H

OCH₃ OCH₂CH₃ H 447 —H

OCH₃ OCH₂CH₃ H 448 —H

OCH₃ OCH₂CH₃ H 449 —H

OCH₃ OCH₂CH₃ H 450 —H

OCH₃ OCH₂CH₃ H 451 —H

OCH₃ OCH₂CH₃ H 452 —H

OCH₃ OCH₂CH₃ H 453 —H

OCH₃ OCH₂CH₃ H 454 —H

OCH₃ OH H 455 —H

OCH₃ OH H 456 —H

OCH₃ OH H 457 —H

OCH₃ OH H 458 —H

OCH₃ OH H 459 —H

OCH₃ OH H 460 —H

OCH₃ OH H 461 —H

OCH₃ OH H 462 —H

OCH₃ OH

463 —H

OCH₃ OH Br 464 —H

OCH₃ OH H 465 —H —CH(CH₃)₂ OCH₃ OH H 466 —H —CH₂CH₂CH₃ OCH₃ OHCH₃SO₂—NH— 467 —H

OCH₃ OH H 468 —H

OCH₃ OH H 469 —H

OCH₃ OH H 470 —H —CH₂CH₃ OCH₃ OH H 471 —H

OCH₃ OH H 472 —H

OCH₃ OH H 473 —H

OCH₃ OH H 474 —H

OCH₃ OH H 475 —H

OCH₃ OH H 476 —H

OCH₃ OH H 477 —H

OCH₃ OH H 478 —H

OCH₃ OH H 479 —H —CH₂CH₃ OCH₃ OH H 480 —H

OCH₃ OH H 481 —H

OCH₃ OH H 482 —H

OCH₃ OH H 483 —H

OCH₃ OH H 484 —H

OCH₃ OH H 485 —H

OCH₃ OH H 486 —H —CH₃ OCH₃ OH H 487 —H

OCH₃ OH H 488 —H

OCH₃ OH H 489 —H

OCH₃ OH H 490 —H

OCH₃ OH H 491 —H

OCH₃ OH H 492 —H

OCH₃ OH H 493 —H

OCH₃ OH H 494 —H —CH₂CH₂CH₃ OCH₃ OH H 495 —H —CH₂CH₂CH₂CH₃ OCH₃ OH H 496—H

OCH₃ OH H 497 —H

OCH₃ OH H 498 —H —CH₂CH₂CH₃ OCH₃ OH H 499 —H —(CH₂)₅CH₃ OCH₃ OH H 500 —H—CH═CH₂ OCH₃ OH H 501 —H —CH₂—C≡CH OCH₃ OH H 502 —H

OCH₃ OH H 503 —H

OCH₃ OH H 504 —H

OCH₃ OH H 505 —H

OCH₃ OH H 506 —H

OCH₃ OH H 507 —H

OCH₃ OH H 508 —H

OCH₃ OH H 509 —H

OCH₃ OH H 510 —H

OCH₃ OH H 511 —H

OCH₃ OH H 512 —H

OCH₃ OH H 513 —H

OCH₃ OH H 514 —H

OCH₃ OH H 515 —H

OCH₃ OH H 516 —H

OCH₃ OH H 517 —H

OCH₃ OH H 518 —H

OCH₃ OH CH₃CH₂SO₂NH— 519 —H

OCH₃ OH CH₃(CH₂)₂SO₂NH— 520 —H

OCH₃ OH CH₃(CH₂)₃SO₂NH— 521 —H

OCH₃ OH (CH₃)₃CSO₂NH— 522 —H

OCH₃ OH (CH₃)₂CHSO₂NH— 523 —H

OCH₃ OH

524 —H

OCH₃ OCH₃ CH₃CH₂SO₂NH— 525 —H

OCH₃ OCH₃ CH₃(CH₂)₂SO₂NH— 526 —H

OCH₃ OCH₃ CH₃(CH₂)₃SO₂NH— 527 —H

OCH₃ OCH₃ (CH₃)₃CSO₂NH— 528 —H

OCH₃ OCH₃ (CH₃)₂CHSO₂NH— 529 —H

OCH₃ OCH₃

530 —H

OCH₃ OCH₂CH₃ CH₃CH₂SO₂NH— 531 —H

OCH₃ OCH₂CH₃ CH₃(CH₂)₂SO₂NH— 532 —H

OCH₃ OCH₂CH₃ CH₃(CH₂)₃SO₂NH— 533 —H

OCH₃ OCH₂CH₃ (CH₃)₃CSO₂NH— 534 —H

OCH₃ OCH₂CH₃ (CH₃)₂CHSO₂NH— 535 —H

OCH₃ OCH₂CH₃

536 —H

OCH₃ OH CH₃CH₂SO₂NH— 537 —H

OCH₃ OH CH₃CH₂)₂SO₂NH— 538 —H

OCH₃ OH CH₃(CH₂)₃SO₂NH— 539 —H

OCH₃ OH (CH₃)₃CSO₂NH— 540 —H

OCH₃ OH (CH₃)₂CHSO₂NH— 541 —H

OCH₃ OH

542 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃ —OCH₂CO₂H 543 —H —CH₂CH₂CH₃ —OCH₂CH₃—OCH₂Ph —OCH₂CO₂H 544 —H

—OCH₂CH₃ —OCH₂CH₃ —OCH₂CO₂H 545 —H

—OCH₂CH₃ —OCH₂Ph —OCH₂CO₂H 546 —H

—OCH₂CH₃ —OCH₂Ph —OCH₂CO₂H 547 —H

—OCH₂CH₃ —OCH₂CH₃ —OCH₂CO₂H 548 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃ —OCH₂CO₂H549 —H -isopropyl —OCH₂CH₃ —OCH₂CH₃ —OCH₂CO₂H 550 —H -isobutyl —OCH₂CH₃—OCH₂CH₃ —OCH₂CO₂H 551 —H -sec-butyl —OCH₂CH₃ —OCH₂CH₃ —OCH₂CO₂H 552 —H—CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —OCH₂CO₂H 553 —H —CH₂CH₂CH₂Cl —OCH₂CH₃—OCH₂CH₃ —OCH₂CO₂H 554 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃

555 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂Ph

556 —H

—OCH₂CH₃ —OCH₂CH₃

557 —H

—OCH₂CH₃ —OCH₂Ph

558 —H

—OCH₂CH₃ —OCH₂Ph

559 —H

—OCH₂CH₃ —OCH₂CH₃

560 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃

561 —H -isopropyl —OCH₂CH₃ —OCH₂CH₃

562 —H -isobutyl —OCH₂CH₃ —OCH₂CH₃

563 —H -sec-butyl —OCH₂CH₃ —OCH₂CH₃

564 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃

565 —H —CH₂CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃

566 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH(CH₃)₂ —NHSO₂CH₃ 567 —H

—OCH₂CH₃ —OCH(CH₃)₂ —NHSO₂CH₃ 568 —H

—OCH₂CH₃ —OCH(CH₃)₂ —NHSO₂CH₃ 569 —H -n-Butyl —OCH₂CH₃ —OCH(CH₃)₂—NHSO₂CH₃ 570 —H -isopropyl —OCH₂CH₃ —OCH(CH₃)₂ —NHSO₂CH₃ 571 —H-isobutyl —OCH₂CH₃ —OCH(CH₃)₂ —NHSO₂CH₃ 572 —H -sec-butyl —OCH₂CH₃—OCH(CH₃)₂ —NHSO₂CH₃ 573 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH(CH₃)₂ —NHSO₂CH₃ 574—H —CH₂CH₂CH₂Cl —OCH₂CH₃ —OCH(CH₃)₂ —NHSO₂CH₃ 575 —H —CH₂CH₂CH₃ —OCH₂CH₃—OCH(CH₃)Et —NHSO₂CH₃ 576 —H -isobutyl —OCH₂CH₃ —OCH(CH₃)Et —NHSO₂CH₃577 —H -sec-butyl —OCH₂CH₃ —OCH(CH₃)Et —NHSO₂CH₃ 578 —H —CH₂CH₂CH₃—OCH₂CH₃ —OCH₂CH₃

579 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂Ph

580 —H

—OCH₂CH₃ —OCH₂CH₃

581 —H

—OCH₂CH₃ —OCH₂Ph

582 —H

—OCH₂CH₃ —OCH₂Ph

583 —H

—OCH₂CH₃ —OCH₂CH₃

584 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃

585 —H -isobutyl —OCH₂CH₃ —OCH₂CH₃

586 —H -sec-butyl —OCH₂CH₃ —OCH₂CH₃

587 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃

588 —H —CH₂CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃

589 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₂CO₂Et 590 —H —CH₂CH₂CH₃—OCH₂CH₃ —OCH₂Ph —NHSO₂CH₂CO₂Et 591 —H

—OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₂CO₂H 592 —H

—OCH₂CH₃ —OCH₂Ph —NHSO₂CH₂CO₂Et 593 —H

—OCH₂CH₃ —OCH₂Ph —NHSO₂CH₂CO₂H 594 —H

—OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₂CO₂Et 595 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃—NHSO₂CH₂CO₂Et 596 —H -propyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₂CO₂H 597 —H-isobutyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₂CO₂Et 598 —H -sec-butyl —OCH₂CH₃—OCH₂CH₃ —NHSO₂CH₂CO₂Et 599 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃—NHSO₂CH₂CO₂Et 600 —H —CH₂CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₂CO₂Et 601—H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃ —NCH₃SO₂CH₃ 602 —H —CH₂CH₂CH₃ —OCH₂CH₃—OCH₂Ph —NCH₃SO₂CH₃ 603 —H

—OCH₂CH₃ —OCH₂CH₃ —NCH₃SO₂CH₃ 604 —H

—OCH₂CH₃ —OCH₂Ph —NCH₃SO₂CH₃ 605 —H

—OCH₂CH₃ —OCH₂Ph —NCH₃SO₂CH₃ 606 —H

—OCH₂CH₃ —OCH₂CH₃ —NCH₃SO₂CH₃ 607 —H -n-butyl —OCH₂CH₃ —OCH₂CH₃—NCH₃SO₂CH₃ 608 —H -isopropyl —OCH₂CH₃ —OCH₂CH₃ —NCH₃SO₂CH₃ 609 —H-isobutyl —OCH₂CH₃ —OCH₂CH₃ —NCH₃SO₂CH₃ 610 —H -sec-butyl —OCH₂CH₃—OCH₂CH₃ —NCH₃SO₂CH₃ 611 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —NCH₃SO₂CH₃ 612—H —CH₂CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —NCH₃SO₂CH₃ 613 —H —CH₂CH₂CH₃ —OCH₂CH₃—OCH₂CH₃ —NHSO₂i-Pr 614 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂Ph —NHSO₂i-Pr 615 —H

—OCH₂CH₃ —OCH₂CH₃ —NHSO₂i-Pr 616 —H

—OCH₂CH₃ —OCH₂Ph —NHSO₂i-Pr 617 —H

—OCH₂CH₃ —OCH₂Ph —NHSO₂i-Pr 618 —H

—OCH₂CH₃ —OCH₂CH₃ —NHSO₂i-Pr 619 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃—NHSO₂i-Pr 620 —H -isopropyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂i-Pr 621 —H-isobutyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂i-Pr 622 —H -sec-butyl —OCH₂CH₃—OCH₂CH₃ —NHSO₂i-Pr 623 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂i-Pr 624 —H—CH₂CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂i-Pr 625 —H —CH₂CH₂CH₃ —OCH₂CH₃—OCH₂CH₃ —NHSO₂Ph 626 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂Ph —NHSO₂Ph 627 —H

—OCH₂CH₃ —OCH₂CH₃ —NHSO₂Ph 628 —H

—OCH₂CH₃ —OCH₂Ph —NHSO₂Ph 629 —H

—OCH₂CH₃ —OCH₂Ph —NHSO₂Ph 630 —H

—OCH₂CH₃ —OCH₂CH₂ —NHSO₂Ph 631 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂Ph632 —H -isopropyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂Ph 633 —H -isobutyl —OCH₂CH₃—OCH₂CH₃ —NHSO₂Ph 634 —H -sec-butyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂Ph 635 —H—CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂Ph 636 —H —CH₂CH₂CH₂Cl —OCH₂CH₃—OCH₂CH₃ —NHSO₂Ph 637 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃

638 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂Ph

639 —H

—OCH₂CH₃ —OCH₂CH₃

640 —H

—OCH₂CH₃ —OCH₂Ph

641 —H

—OCH₂CH₃ —OCH₂Ph

642 —H

—OCH₂CH₃ —OCH₂CH₃

643 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃

644 —H -isopropyl —OCH₂CH₃ —OCH₂CH₃

645 —H -isobutyl —OCH₂CH₃ —OCH₂CH₃

646 —H -sec-butyl —OCH₂CH₃ —OCH₂CH₃

647 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃

648 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃

649 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂Ph

650 —H

—OCH₂CH₃ —OCH₂CH₃

651 —H

—OCH₂CH₃ —OCH₂Ph

652 —H

—OCH₂CH₃ —OCH₂Ph

653 —H

—OCH₂CH₃ —OCH₂CH₃

654 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃

655 —H -isopropyl —OCH₂CH₃ —OCH₂CH₃

656 —H -isobutyl —OCH₂CH₃ —OCH₂CH₃

657 —H -sec-butyl —OCH₂CH₃ —OCH₂CH₃

658 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃

659 —H —CH₂CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃

660 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃ —OCHMeCO₂H 661 —H —CH₂CH₂CH₃—OCH₂CH₃ —OCH₂Ph —OCHMeCO₂H 662 —H

—OCH₂CH₃ —OCH₂CH₃ —OCHMeCO₂H 663 —H

—OCH₂CH₃ —OCH₂Ph —OCHMeCO₂H 664 —H

—OCH₂CH₃ —OCH₂Ph —OCHMeCO₂H 665 —H

—OCH₂CH₃ —OCH₂CH₃ —OCHMeCO₂H 666 —H -n-Butyl —OCH₂CH₃ —OCH₂CH₃—OCHMeCO₂H 667 —H -isopropyl —OCH₂CH₃ —OCH₂CH₃ —OCHMeCO₂H 668 —H-isobutyl —OCH₂CH₃ —OCH₂CH₃ —OCHMeCO₂H 669 —H -sec-butyl —OCH₂CH₃—OCH₂CH₃ —OCHMeCO₂H 670 —H —CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —OCHMeCO₂H 671 —H—CH₂CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —OCHMeCO₂H 672 —H —CH₂CH₂CH₃ —OCH₂CH₃—OCH₂CH₃ —NHSO₂CH₃ 673 —H

—OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₃ 674 —H

—OCH₂CH₃ —OCH₂Ph —NHSO₂CH₃ 675 —H

—OCH₂CH₃ —OCH₂Ph —NHSO₂CH₃ 676 —H

—OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₃ 677 —H -propyl —OCH₂CH₃ —OH —NHSO₂CH₃ 678 —H-isopropyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₃ 679 —H -isobutyl —OCH₂CH₃—OCH₂CH₃ —NHSO₂CH₃ 680 —H -sec-butyl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₃ 681 —H—CH₂CH₂Cl —OCH₂CH₃ —OCH₂CH₃ —NHSO₂CH₃ 682 —H —CH₂CH₂CH₂Cl —OCH₂CH₃—OCH₂CH₃ —NHSO₂CH₃ 683 —OCH₂CH₃ —CH₂CH₂CH₃ —OCH₂CH₃ —H —H 684 —OCH₂CH₃—CH₂CH₃ —OCH₂CH₃ —H —H 685 —OCH₂CH₃ —CH₂CH₂CH₂CH₃ —OCH₂CH₃ —H —H 686—OCH₂CH₃

—OCH₂CH₃ —H —H 687 —OCH₂CH₃

—OCH₂CH₃ —H —H 688 —OCH(CH₃)₂ —CH₂CH₂CH₃ —OCH₂CH₃ —H —H 689 —OCH(CH₃)₂—CH₂CH₃ —OCH₂CH₃ —H —H 690 —OCH(CH₃)₂ —CH₂CH₂CH₂CH₃ —OCH₂CH₃ —H —H 691—OCH(CH₃)₂

—OCH₂CH₃ —H —H 692 —OCH(CH₃)₂

—OCH₂CH₃ —H —H 693

—OCH₂CH₃ —H —H 694

—CH₂CH₂CH₃ —OCH₂CH₃ —H —H 695 —H

—OCH₂CH₃ —OCH₂CH₃

696 —H

—OCH₂CH₃ —OCH₂CH₃

697 —H

—OCH₂CH₃ —OCH₂CH₃

698 —H

—OCH₂CH₃ —OCH₂CH₃

699 —H

—OCH₂CH₃ —OCH₂CH₃

700 —H —CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃

701 —H —CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃

702 —H —CH₂CH₂CH₂CH₃ —OCH₂CH₃ —OCH₂CH₃

703 —H

—OCH₂CH₃ —OCH₂CH₃

704 —H —CH₂CH₂CO₂H —OCH₂CH₃ —OCH₂CH₃

705 —H —CH₂CH₂CONH₂ —OCH₂CH₃ —OCH₂CH₃

706 —H —CH₂CH₂CH₂OH —OCH₂CH₃ —OCH₂CH₃

707 —H

—OCH₂CH₃ —OCH₂CH₃

708 —H

—OCH₂CH₃ —OCH₂CH₃

709 —H

—OCH₂CH₃ —OCH₂CH₃

710 —H

—OCH₂CH₃ —OCH₂CH₃

711 —H

—OCH₂CH₃ —OCH₂CH₃

712 —H

—OCH₂CH₃ —OCH₂CH₃

713 —H

—OCH₂CH₃ —OCH₂CH₃

714 —H

—OCH₂CH₃ —OCH₂CH₃

715 —H

—OCH₂CH₃ —OCH₂CH₃

716 —H

—OCH₂CH₃ —OCH₂CH₃

717 —H

—OCH₂CH₃ —OCH₂CH₃

718 —H

—OCH₂CH₃ —OCH₂CH₃

719 —H

—OCH₂CH₃ —OCH₂CH₃

720 —H

—OCH₂CH₃ —OCH₂CH₃

721 —H

—OCH₂CH₃ —OCH₂CH₃

722 —H

—OCH₂CH₃ —OCH₂CH₃

723 —H

—OCH₂CH₃ —OCH₂CH₃

724 —H

—OCH₂CH₃ —OCH₂CH₃

725 —H

—OCH₂CH₃ —OCH₂CH₃

726 —H

—OCH₂CH₃ —OCH₂CH₃

727 —H

—OCH₂CH₃ —OCH₂CH₃

728 —H

—OCH₂CH₃ —OCH₂CH₃

729 —H

—OCH₂CH₃ —OCH₂CH₃

730 —H

—OCH₂CH₃ —OCH₂CH₃

The compounds of the invention contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses described above mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Diastereomeric compounds may be separated bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated using the same techniques or others known inthe art. Each of the asymmetric carbon atoms may be in the R or Sconfiguration and both of these configurations are within the scope ofthe invention.

UTILITY

It has been discovered that the compounds of the invention when made andselected as disclosed herein are inhibitors of serine protease enzymes,for example, factor VIIa, TF/factor VIIa, factor Xa, kallikrein and/orthrombin. These compounds are capable of inhibiting the catalyticactivity of these enzymes and as such function to inhibit thecoagulation cascade and prevent or limit coagulation and/or theformation of thrombi or emboli in blood vessels and/or increase the timeof coagulation of blood. The compounds of the present invention,therefore, inhibit the ability of TF/factor VIIa to convert factor X tofactor Xa, inhibit the ability of factor Xa to convert prothrombin tothrombin (factor IIa); and/or the ability of thrombin to convertfibrinogen to fibrin monomers.

The selectivity of the compounds of the invention as inhibitors of theseenzymes can be determined using Ki values as described in the examplesbelow. Representative selectivities are shown in the tables below.

R1 X R9 R10 Z2 R11 Ki(TFVIIa) uM Ph C═O OEt OiPr H H 0.003 Pr CH2 OEtOCH2Ph H NHSO2Me 0.004 Ph C═O OEt OEt H H 0.005 Ph C═O OEt H OEt H 0.007R1 X R9 R10 Z2 R11 Ki(IIa) uM Ph CH2 OMe OCH(CH2Cl)Ph H H 0.0012-thiophene CH2 OMe OCH2Ph H H 0.016 Ph C═O OEt OiPr H H 0.113 Pr CH2OMe OCH(CH2Cl)Ph H H 0.001 R1 X R9 R10 Z2 R11 Ki(Kallikrein) uM Pr CH2OEt OiBu H NHSO2Pr 0.001 Pr CH2 OEt OiPr H NHSO2Me 0.001 Et C═O OEt OiPrH H 0.011 Ph C═O OEt OEt H H 0.002 R1 X R9 R10 Z2 R11 Ki(Xa) uM Et C═OOEt OiPr H H 0.565 Bu C═O OEt OiPr H H 0.624 Ph C═O OEt OiPr H H 0.898Pr CH2 OMe OCH(CH2Cl)Ph H H 0.140

The anti-coagulant activity of the compounds of the invention can betested using assays. Prothrombin time (PT) and activated partialthromboplastin time (APTT) clotting time assays can be performed inpooled normal plasmas (human or various animal species) followingaddition of increasing concentrations of inhibitors to the plasma.Clotting times are determined using an ACL 300 Automated CoagulationAnalyzer (Coulter Corp., Miami, Fla.) and commercially availablereagents as follows.

PT assay: Aqueous solutions of inhibitor at various concentrations areadded to pooled normal plasma in a ratio of 1 part inhibitor to 9 partsplasma. These mixtures are then added to the analyzer's sample cups.Innovin® (Dade International Inc., Miami, Fla.), a mixture of humanrelipidated tissue factor and Ca⁺⁺ ions is added to the reagent cup.Precise volumes of sample and Innovin® are automatically transferred tocells of an acrylic rotor that is pre-equilibrated to 37 C. Following a2 minute incubation period, coagulation is initiated when the twocomponents are mixed together by centrifugation. Coagulation ismonitored optically and clotting time is reported in seconds. Inagreement with Janson et al. (Janson, T. L., et al., 1984, Haemostasis14: 440-444) relipidated human tissue factor is a potent initiator ofcoagulation in all species tested. In this system, the clotting time ofcontrol plasmas (plasma plus inhibitor diluent) is typically 8 to 10seconds. A curve is fit to the clotting time versus inhibitorconcentration data and the concentration at which the PT is doubledcompared to control plasma is determined for each inhibitor.

APTT assay: Inhibitor and plasma are mixed together and transferred tothe ACL 300 sample cups as described above. Actin FS® and CaCl₂ (DadeInternational Inc., Miami, Fla.), are added to reagent cups 1 and 2respectively. Precise volumes of sample and activator (Actin FS®) areautomatically transferred to cells of a pre-equilibrated rotor (37 C)and mixed by centrifugation. Following a 2 minute activation period,coagulation is initiated by the addition of CaCl₂. Coagulation ismonitored and data calculated as described in the PT method. APTT ofplasma controls is typically 12 to 32 seconds, depending on the speciesof plasma used in the assay.

Representative PT and APTT assay results are shown in Table 3 below.

TABLE 3 Compound No. 2 × PT (μM) 2 × APTT (μM)  7 14 8  13 16 57  33 5.511  72 30 60 589 22 40 596 8 140 628 125 90 672 34 78

The compounds of the invention are useful as diagnostic reagents invitro for inhibiting clotting in blood drawing tubes. The use ofstoppered test tubes having a vacuum therein as a means to draw blood iswell known. Kasten, B. L. “Specimen Collection”, Laboratory TestHandbook, 2nd Ed., Lexi-Comp Inc., Cleveland, PP 16-17, Eds. Jacobs, D.S. et al, 1990. Such vacuum tubes may be free of clot-inhibitingadditives, in which case, they are useful for the isolation of mammalianserum from the blood. They may also contain cloth-inhibiting additives,such as heparin salts, citrate salts or oxalate salts, in which casethey are useful for the isolation of mammalian plasma from the blood.The compounds of the invention may be incorporated into blood collectiontubes and function to inhibit TF/factor VIIa, factor Xa, thrombin and/orkallikrein and to prevent clothing of the mammalian blood drawn into thetubes.

When used in blood collection tubes, the compounds of the invention maybe used alone, as mixtures or in combination with other clottinginhibiting compounds known in this art. The amount of the compound ofthe invention should be an amount sufficient to prevent or inhibit theformation of a clot when blood is drawn into the tube. These compoundsmay be introduced into the tubes in the same manner as knownclot-inhibiting compounds such as heparin salts. Liquids are usuallylyophilized using known methods. Typically, the tubes will contain about2 to about 10 ml of mammalian blood and the compounds are added in anamount sufficient to prevent coagulation of this amount of blood. Asuitable concentration is about 10-1000 nM.

These compounds also inhibit the formation of emboli and thrombi in thecirculatory system in mammals and therefore are useful in vivo.Thromboembolic disorders have been shown to be directly releated to thesusceptibility of the mammal to formation of emboli and thrombi. Forexample, the formation of a thrombus in a veinous vessel results inthrombophlebitis, which is typically treated with rest and theadministration of anticoagulants. Other conditions which can be treatedwith the anticoagulant compounds of the invention include,thrombolymphangitis, thrombosinusitis, thromboendocarditis,thromboangiitis, and thromboarteritis.

Mammals exposed to medical procedures such as angioplasty andthrombolytic therapy are particularly susceptible to thrombus formation.The compounds of the present invention can be used to inhibit thrombusformation following angioplasty. They may also be used in combinationwith antithrombolytic agents such as tissue plasminogen activator andits derivatives (U.S. Pat. Nos. 4,752,603; 4,766,075; 4,777,043; EP 199574; EP 238 304; EP 228 862; EP 297 860; PCT WO89/04368; PCTWO89/00197), streptokinase and its derivatives, or urokinase and itsderivatives to prevent arterial reocclusion following thrombolytictherapy. When used in combination with the above thrombolytic agents,the compounds of the present invention may be administered prior to,simultaneously with, or subsequent to the antithrombolytic agent.

Mammals exposed to renal dialysis, blood oxygenation, cardiaccatheterization and similar medical procedures as well as mammals fittedwith certain prosthetic devices are also susceptible to thromboembolicdisorders. Physiologic conditions, with or without known cause may alsolead to thromboembolic disorders.

Thus, the compounds described herein may be useful in treatingthromboembolic disorders in mammals. The compounds described herein mayalso be used as adjuncts to anticoagulant therapy, for example incombination with aspirin, heparin or warfarin and other anticoagulantagents. The various coagulation disorders described above are treatedwith the compounds of the invention in such a fashion as to preventbleeding as a result of the disorder. The application of the compoundsdescribed herein for these and related disorders will be apparent tothose skilled in the art.

Compounds of this invention are also useful as intermediates generally,or as precursors of coagulation serine protease inhibitors and thus inaddition to treating cardiovascular disease, these compounds may beusefully employed in metastatic disease, or for any disease whereinhibition of coagulation is indicated.

Typically, the inhibitors used in the method of this invention isformulated by mixing it at ambient temperature at the appropriate pH,and at the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed. The pH of the formulation depends mainly onthe particular use and the concentration of compound, but preferablyranges anywhere from about 3 to about 8. Formulation in an acetatebuffer at pH 5 is a suitable embodiment.

The inhibitory compound for use herein is preferably sterile. Thecompound ordinarily will be stored as a solid composition, althoughlyophilized formulations or aqueous solutions are acceptable.

The composition of the invention will be formulated, dosed, andadministered in a fashion consistent with good medical practice. Factorsfor consideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. The“therapeutically effective amount” of the compound to be administeredwill be governed by such considerations, and is the minimum amountnecessary to prevent, ameliorate, or treat the coagulation factormediated disorder. Such amount is preferably below the amount that istoxic to the host or renders the host significantly more susceptible tobleeding.

As a general proposition, the initial pharmaceutically effective amountof the inhibitor administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, preferably about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day.

The compound of the invention is administered by any suitable means,including oral, topical, transdermal, parenteral, subcutaneous,intraperitoneal, intrapulmonary, and intranasal, and, if desired forlocal immunosuppressive treatment, intralesional administration(including perfusing or otherwise contacting the graft with theinhibitor before transplantation). Parenteral infusions includeintramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration.

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention. All patent and literature citations areherein incorporated by reference in their entirety.

EXAMPLES

The compounds of the invention can be prepared generally by the reactionscheme shown below. Compounds other than the specific product shown areprepared as described above using corresponding starting materials. Forexample, additional compounds can be prepared by using differentstarting styrene compounds, which are readily prepared from commerciallyavailable starting compounds and standard reactions which are well knownin this art.

Example 1

4-benzyloxy-3-methoxy-styrene (10 g, 42 mmoles) was dissolved indichloromethane (400 ml). Solid potassium bicarbonate (11 g, 110 mmoles)was added and the reaction cooled to zero degrees Celsius.Meta-chloroperbenzoic acid (12 g, ca. 42 mmoles) was added and thereaction allowed to warm to room temperature and stirred for 16 hours.The reaction was monitored by thin-layer chromatography. An additionalamount of meta-chloroperbenzoic acid (4 g) was added and the reactionstirred for an additional 4 hours to completely consume startingmaterial. The reaction was poured into a separtory funnel and washedfirst with water, then with sodium bicarbonate and finally with NaOH.The organic layer was separated and dried over anhydrous sodium sulfate.The solution was filtered and the solvent removed in vacuo to yieldapproximately 11 g of crude product.

The crude product was then dissolved in acetonitrile (60 ml) and lithiumperchlorate (8.5 g, 80 mmoles) added. The suspension was stirred forfive minutes at which time the reaction became homogeneous.4-amino-benzonitrile (9.5 g, 80 mmoles) was added and the reactionheated to 60 degrees C. for 12 hours. Thin layer chromatography showedthe presence of a new product at lower Rf. The solvent was removed invacuo and the residue taken up in ethyl acetate, washed with water andried over anhydrous sodium sulfate. The crude product was thensubmitted to flash chromatography (hexanes:ethyl acetate 1:1) to yield 6grams of4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-hydroxy-ethylamino]-benzonitrileA. ¹HNMR(CDCl₃): 7.3-7.45, (m, 7H), 6.8 (m, 3H), 6.5 (d, 2H), 5.18 (s,2H), 4.42 (m, 1H), 3.95 (dd, 1H), 3.85 (s, 3H), 3.8 (dd, 1H).

4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-hydroxy-ethylamino]-benzonitrile A(470 mg, 1.25 mmoles), phthalimide (1.47 g, 10 mmoles), andtriphenylphosphine (787 mg, 3 mmoles) were added to 40 ml oftetrahydrofuran. The mixture was stirred for 10 minutes and then cooledto zero degrees Celsius. Diisopropylazodiacarboxylate (DIAD, 0.6 ml, 3mmoles) was then added slowly. The reaction was allowed to stir 1 hour.TLC indicated new product. The solvent was removed in vacuo and theresidue taken up in 50 ml of ethyl acetate. The solution was washedthree times with 2N sodium hydroxide and twice with water. The organiclayer was separated, dried over anhydrous sodium sulfate and filtered.The solvent was removed in vacuo and the residue submitted to flashchromatography (hexanes:ethyl acetate, 1:1) to yield 478 mg of product4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrileB (76% yield). ¹HNMR(CDCl₃): 7.85 (m, 2H,), 7.75 (m, 2H), 7.23-7.45 (m,9H), 6.9 (m, 3H), 6.42 (d, 2H), 5.45 (d, 1H), 5.15 (s, 2H), 4.62 (m,1H), 4.0 (m, 2H), 3.83 (s, 3H).

4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrileB was then dissolved in ethanol (60 ml) and hydrazine hydrate (2 g) wasadded. The solution was heated to 60-70 degrees C. for 1.5 hours. TLCshowed reaction was complete. The suspension was filtered to removeby-product and the ethanol removed in vacuo. The residue was submittedto flash chromatography on silica gel (ethyl acetate: 2N NH3 inmethanol, 9:1) to yield 372 mg of4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzonitrile D(100%). ¹NMR(CDCl₃): 7.3-7.45 (m, 7H), 6.32 (m, 3H), 6.5 (d, 2H), 5.52(d, 1H), 4.3 (q, 1H), 3.83 (s, 3H), 3.08 (m, 2H), 1,95 (s, 2H).

4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzonitrile D(300 mg, 0.8 mmoles) was dissolved in ethanol (3 ml) andhydroxylamine-hydrochloride (350 mg, 5 mmoles) and triethylamine (1 ml,5.7 mmoles) were added. The reaction was heated to 65-70 degrees C. for2 hours. The residue was taken up in ethyl acetate and water. Theorganic layer was separated, dried over anhydrous sodium sulfate andfiltered. The solvent was removed in vacuo and replaced with 4 mlmethanol with 0.5 ml acetic acid. Raney nickel (ca. 300 ul suspension insodium hydroxide, Aldrich) was added and the reaction placed under ahydrogen atmosphere. The reaction was stirred vigorously for 3 hours,the catalyst filtered off and the solvent removed in vacuo. The crudeproduct was purified by flash chromatography on silica gel (ethylacetate:acetone:methanol:ammonia, 2:1:1:0.05) to yield 160 mgs of4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzamidine E.MS (M+H)=391.

4-[2-Amino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzamidine E(20 mg, 0.03 mmoles) was dissolved in acetonitrile (2 ml) containingtriethylamine (17 ul, 0.12 mmoles) and water (0.3 ml). To this was addedthe desired sulfonyl chloride having a formula ClSO₂R(0.03 mmoles) andthe reaction stirred for 4 hours. The solvent was removed in vacuo andthe compounds purified by reverse-phase preparative HPLC (gradientacetonitrile/water with 0.1% trifluoroacetic acid) to yield the finalproduct upon lyophilization.

Examples 2a-2dd

Using an analogous procedure, other compounds of the invention wereprepared, including:

a)4-[Benzenesulfonylamino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzamidine:MS (M+H)=531,

b)N-{4-[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethylsulfamoyl]-phenyl}-acetamide:MS (M+H)=588,

c)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-nitro-benzenesulfonylamino)ethylamino]-benzamidine:MS (M+H)=576,

d)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-fluoro-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=549,

e)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-fluoro-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=565,

f)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(3-nitro-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=576,

g)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(2,5-dichloro-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=599,

h)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(2-bromo-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=609, 611,

i)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-bromo-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=609,

j)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-isopropyl-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=573,

k)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-phenylmethanesulfonylamino-ethylamino]-benzamidine:MS (M+H)=545,

l)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carboxy-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=575,

m)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(3-carboxy-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=575,

n)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(2,4-dinitro-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=621,

o)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(2,3,5,6-tetramethyl-benzenesulfonylamino)ethylamino]-benzamidine:MS (M+H)=587,

p)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(3,5-dichloro-2-hydroxy-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=615,

q)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(3,4-dimethoxy-benzenesuifonylamino)-ethylamino]-benzamidine:MS (M+H) 591,

r)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(thiophene-2-sulfonylamino)-ethylamino]-benzamidine:MS(M+H)=537,

s)N-{5-[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethylsulfamoyl]-4-methyl-thiazol-2-yl}-acetamide:MS(M+H)=595,

t)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(naphthalene-2-sulfonylamino)-ethylamino]-benzaidine:MS (M+H)=581,

u)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(naphthatene-1-sulfonylamino)-ethylamino]-benzamidine:MS (M+H)=581,

v)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(2-phenyl-ethenesulfonylamino)ethylamino]-benzamidine:MS (M+H)=557,

w)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(3-trifluoromethyl-benzenesulfonylamino)ethylamino]-benzamidine:MS (M+H)=599,

x)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(2,3,4,5,6-pentafluoro-benzenesulfonylamino)-ethylamino]-benzamidine:MS (M+H)=521,

y)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-methanesulfonylamino-ethylamino]-benzamidine:MS(M+H)=469,

z)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-ethanesulfonylamino-ethylamino]-benzamidine:MS(M+H)=483,

aa)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-propanesulfonylamino-ethylamino]-benzamidine:MS(M+H)=497,

bb)4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-butanesulfonylamino-ethylamino]-benzaidine:MS(M+H)=511,

cc)[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)ethylsulfamoyl]-aceticacid ethyl ester MS (M+H)=541,

dd)[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethylsulfamoyl]-aceticacid.

Example 3

4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)ethylamino]-benzonitrileB (1.8 g) was dissolved in a mixture of ethanol (50 ml), acetic acid (3ml), methanol (5 ml), and ethyl acetate (5 ml). This solution was addedto a Parr flask containing 10% Pd/C (500 mg) and hydrogenated at 35 psifor 16 hours. The catalyst was removed by filtration through Celite andthe solvent removed in vacuo to provide 1 g of the product4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-1-(4-hydroxy-3-methoxy-phenyl)-ethylamino]-benzonitrile(68%).

4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-1-(4-hydroxy-3-methoxy-phenyl)-ethylamino]-benzonitrile(1 g, 2.43 mmoles) was dissolved in tetrahydrofuran (30 ml) andtriphenylphosphine (1.27 g, 4.84 mmoles), (S)-2-chloro-1-phenyl-ethanol(1.13 g, 7.26 mmoles) added. The reaction was cooled to 0° C. anddiethylazodicarboxylate (0.842 g, 4.8 mmoles) added. The reactiontemperature was allowed to come to room temperature and the reactionstirred for 2.5 hours. The solvent was removed in vacuo and the residuetaken up in ethyl acetate, washed with 0.5 N sodium hydroxide severaltimes, washed once with brine and dried over anhydrous sodium sulfate.The crude product was purified by flash chromatography on silica gel(30% ethyl acetate in hexanes) to yield 1.1 g of4-[1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile,(82%).

4-[1-[4-(2-Chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile (0.5 g)was dissolved in ethanol (40 ml) and hydrazine hydrate (0.14 g) added.The reaction was heated at 65° C. for 2 hours. The solvent was removedand replaced with ethyl acetate. The solution was washed twice withwater and once with brine. The solution was dried over anhydrous sodiumsulfate and the solvent removed in vacuo to yield 318 mg of desiredamine4-{2-Amino-1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzonitrile,(83%).

4-{2-Amino-1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzonitrile,(0.1 g, 0.237 mmoles) was dissolved in dichloromethane (6 ml) andtriethylamine (34 ul, 0.3 mmoles) added. Phenyl sulfonylchloride (46 ul,0.26 mmoles) was added and the reaction stirred for 90 minutes. Thereaction was diluted with dichloromethane and washed once with sat.sodium bicarbonate and once with water. The solution was dried oversodium sulfate and the solvent removed in vacuo. The product waspurified by silica gel to yield 100 mg of desired productN-[2-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(4-cyano-phenylamino)-ethyl]-benzenesulfonamide.

N-[2-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(4-cyano-phenylamino)-ethyl]-benzenesulfonamide(100 mg 0.18 mmoles) was dissolved in ethanol (3 ml) andhydroxylaminehydrochloride (62 mg, 0.89 mmoles) added. To this was addedtriethylamine (90 mg, 0.89 mmoles) and later potassium carbonate (62mg). The reaction was heated to 80° C. for 48 hours. The reaction wascooled and the solvent removed in vacuo. The residue was taken up inethyl acetate and washed twice with water and once with brine. Thesolution was dried over sodium sulfate and the solvent removed. Thecrude intermediate was dissolved in methanol (4 ml) and a few drops ofacetic acid added. Approximately 50-100 mg of Raney nickel suspended insodium hydroxide (Aldrich) was added and the reaction placed under anatmosphere of hydrogen. The suspension was stirred vigorously for 8hours, the catalyst filtered off and the solvent removed in vacuo. Thecrude product was purified by reverse-phase chromatography to yield4-{2-benzenesulfonylamino-1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzamidine(32 mg). MS(M+H)=579.

Example 4

4-{2-propanesulfonylamino-1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzamidinewas prepared similarly to Example 2, except propanesulfonyl chloride wassubstituted for benzenesulfonyl chloride in the reaction with4-{2-amino-1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzonitrile.MS(M+H)=545.

Example 5

4-Benzyloxy-5-methoxy-2-nitrobenzaldehyde (12.2 g 42 mmoles) and4-aminobenzonitrile (5 g, 42 mmoles) were dissolved in methanol (165 ml)and stirred for two hours and then heated to 60° C. for 30 minutes. Thereaction was allowed to cool to room temperature and benzyl isonitrile(5 g. 42 mmoles) added. The reaction was cooled to 0° C. and borontrifluoroetherate (16 ml, 126 mmoles) added dropwise over five minutes.The reaction was stirred at 0° C. for 20 minutes and then allowed tocome to room temperature and then stirred at ambient temperature for twohours. Water (4 ml) was added and the mixture stirred at roomtemperature overnight. A yellow precipitate was evident the next morningand the solid filtered off. The solid was washed with methanol and airdried to yield 8 grams of the desired product. The solvent from thefiltrate was removed in vacuo and replaced with ethyl acetate. Thesolution was washed with water and saturated sodium bicarbonate, driedover anhydrous magnesium sulfate and the solvent removed. The crudematerial was submitted to flash chromatography (hexanes:ethyl acetate,1:1) to yield an additional 7 g of the desired product(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-(4-cyano-phenylamino)-acetic acidmethyl ester. ¹HNMR(CDCl₃): 7.68 (s, 1H), 7.4 (m, 7H), 7.0 (s, 1H), 6.61(d, 2H), 6.2 (s, 1H), 5.2 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H).

(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-(4-cyano-phenylamino)-acetic acidmethyl ester (4.5 g, 10 mmole) was dissolved in dimethoxyethane andlithium borohydride (0.210 g, 10 mmole) added. The reaction was heatedto reflux for three hours and cooled to room temperature. The reactionwas quenched with water containing acetic acid and diluted with ethylacetate. After transferring to a separatory funnel, the organic layerwas washed with water several times. The organic layer was dried overanhydrous sodium sulfate, filtered and the solvent removed. The crudematerial was then submitted to flash chromatography to yield 3.1 g of4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-hydroxy-ethylamino]-benzonitrile(74%). ¹HNMR(CDCl₃):7.77 (s, 1H), 7.3-7.5 (m, 7H), 7.15 (s, 1H), 6.42(d, 2H), 5.4 (bs, 1H), 5.18 (dd AB syst., 2H), 4.15 (dd, 1H), 3.83 (s,3H), 3.79-3.86 (dd, 1H).

4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-hydroxy-ethylamino]-benzonitrile(3.1 g, 7.4 mmoles) was dissolved in tetrahydrofuran (120 ml) andtriphenylphosphine (5.9 g, 22 mmoles) and phthalimide (5.4 g, 37 mmoles)added. The reaction was cooled to 0 C and diisopropylazadicarboxylate(DIAD, 4.6 g) added dropwise. The reaction was allowed to come to roomtemperature and stirred overnight. The solvent was removed in vacuo andreplaced with ethyl acetate. The solution was washed with 1 N NaOHseveral times and dried over anhydrous sodium sulfate. Flashchromatography (hexanes:ethyl acetate, 1:1) provided the desiredmaterial with some DIAD still present. The solid was washed severaltimes with ethanol to yield 3.2 g of the desired phthalimide4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile(3.2 g,). ¹HNMR(CDCl₃): 7.83 (m, 2H), 7.75 (m, 2H), 7.37 (m, 7H), 6.91(s, 1H), 6.41 (d, 2H), 6.17 (d, 1H), 5.65 (m, 1H), 5.18 (s, 2H), 4.27(m, 2H), 3.61 (s, 3H).

4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile(2.7 g, 5 mmoles) was dissolved in ethanol (100 ml) and hydrazinehydrate (0.65 ml, 20 mmoles) added. The reaction was heated to 60° C.for 3 hours then at room temperature for 48 hours. The solids thatprecipitated were filtered off and the residue submitted to flashchromatography to yield4-[2-Amino-1-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-ethylamino]-benzonitrile(1.5 g). ¹HNMR(CDCl₃): 7.75 (s, 1H), 7.3-7.5 (m, 7H), 7.05 (s, 1H), 6.45(d, 2H), 5.80 (bs, 1H), 5.32 (m, 1H), 5.19 (s, 2H), 3.81 (s, 3H), 3.25(dd, 1H), 3.0 (dd, 1H), 1.65 (bs, 2H).

4-[2-Amino-1-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-ethylamino]-benzonitrile(0.227 g, 0.66 mmoles) was dissolved in dichloromethane (4 ml) andtriethylamine (0.14 ml, 1 mmoles). The reaction was cooled to 0 C and1-propanesulfonyl chloride (0.085 ml, 0.75 mmoles). The reaction wasstirred for 20 minutes and the product purified by flash chromatography(hexanes:ethyl acetate 1:1) to yield 260 mg of desiredproduct—propane-1-sulfonic acid[2-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-2-(4-cyano-phenylamino)-ethyl]-amide.¹HNMR(CDCl₃): 7.77 (s, 1H), 7.3-7.5 (m, 7H), 7.12 (s, 1H), 6.41 (d, 2H),6.0 (d, 1H), 5.3 (m, 1H), 5.17 (dd, A-B, 2H), 4.75 (t, 1H), 3.85 (s,3H), 3.65 (m, 1H), 3.5 (m, 1H), 3.04 (m, 2H), 1.83 (m, 2H), 1.05 (t,3H).

Propane-1-sulfonic acid[2-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-2-(4-cyano-phenylamino)-ethyl]-amide(0.250 g) was dissolved in ethanol (10 ml) and added to Pt/C (5%). Thereaction was placed under a hydrogen atmosphere and stirred vigorouslyfor 3 hours. The catalyst was filtered off and the productchromatographed (hexanes:ethyl acetate 1:2) to yield 133 mg ofPropane-1-sulfonic acid[2-(2-amino-4-benzyloxy-5-methoxy-phenyl)-2-(4-cyano-phenylamino)-ethyl]-amide.¹HNMR(CDCl₃): 7.3-7.45 (m, 7H), 6.71 (s, 1H), 6.52 (d, 2H), 6.3 (s, 1H),5.33 (2, 1H), 5.08 (s, 2H), 5.0 (t, 1H), 4.42 (q, 1H), 3.75 (s, 3H),3.70 (bs, 2H), 3.45 (t, 2H), 2.97 (m, 2H), 1.80 (m, 2H), 1.03 (t, 3H).

Propane-1-sulfonic acid[2-(2-amino-4-benzyloxy-5-methoxy-phenyl)-2-(4-cyano-phenylamino)-ethyl]-amide(133 mg, 0.27 mmoles) was dissolved in dichloromethane and triethylamineadded (0.05 ml, 0.35 mmoles). The reaction was cooled andmethanesulfonyl chloride (0.023 ml, 0.3 mmoles) added dropwise. Thereaction was stirred for two hours and the product purified by flashchromatography (hexanes:ethyl acetate, 1:1). The product was thentaken-up in ethanol and hydroxylamine hydrochloride (35 mg, 0.5 mmoles)added. Sodium ethoxide (48 mg, 0.7 mmoles was added and the reactionheated for 48 hours. The ethanol was removed and water (4 ml) added. Thesolid was filtered off and washed with water. The crude product was thentaken up in 4 ml of methanol with 0.5 ml acetic acid. Raney Nickel (ca.50 mg as a suspension in sodium hydroxide, Aldrich) was added and thereaction placed under a hydrogen atmosphere. The reaction was stirredvigorously for 3 hours and the catalyst filtered off. The crude productwas submitted to reverse-phase preparative chromatography to yield thefinal product4-[1-(4-Benzyloxy-2-methanesulfonylamino-5-methoxy-phenyl)-2-(propane-1-sulfonylamino)-ethylamino]-benzamidine(12 mg): MS (M+H)=590.

Example 6a-6g

Using a procedure analogous to Example 5, the following compounds wereprepared:

a)4-[2-Benzenesulfonylamino-1-(2-benzenesulfonylamino-4-benzyloxy-5-methoxy-phenyl)-ethylamino]-benzamidine.The procedure was the same as above except phenyl sulfonyl chloride wasused instead of propanesulfonyl chloride and methane sulfonyl chloride.MS: (M+H)=686.

b)4-[2-Benzenesulfonylamino-1-(2-benzenesulfonylamino-4-benzyloxy-5-ethoxy-phenyl)ethylamino]-benzamidine.The procedure was the same as above except starting with 3-ethoxy,4-benzyloxy, 6-nitro-benzaldehyde. MS: (M+H)=700.

c)4-[1-(4-Benzyloxy-5-ethoxy-2-methanesulfonylamino-phenyl)-2-(propane-1-sulfonylamino)-ethylamino]benzamidine.The procedure was the same as above except starting with 3-ethoxy,4-benzyloxy, 6-nitro-benzaldehyde. MS (M+H)=604.

d)4-[1-(4,5-Diethoxy-2-methanesulfonylamino-phenyl)-2-(propane-1-sulfonylamino)-ethylamino]-benzamidine.The procedure was the same except starting with 3,4-diethoxy,6-nitrobenzaldehyde. MS (M+H)=542.

e){5-Benzyloxy-2-[1-(4-carbamimidoyl-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4-methoxy-phenylsulfamoyl}-aceticacid ethyl ester. The procedure was the same except usingchlorosulfonyl-acetic acid ethyl ester instead of methanesulfonylchloride. MS: (M+H)=676.

f){5-Benzyloxy-2-[1-(4-carbamimidoyl-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4-methoxy-phenylsulfamoyl}-aceticacid.{5-Benzyloxy-2-[1-(4-carbamimidoyl-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]4-methoxy-phenylsulfamoyl}-aceticacid ethyl ester (10 mg) was dissolved in water (2 ml) andtetrahydrofuran (2 ml) and LiOH added (3 mg). Allowed to stir overnight.Product purified by reverse-phase preparative HPLC. 3 mg MS (M+H)=648.

g)4-[1-(3,4-Dimethoxy-2-methanesulfonylaminophenyl)-2-(propane-1-sulfonylamino)-ethylamino]-benzamidine.This compound was prepared with a similar procedure as described aboveexcept 2-bromo-3,4-dimethoxybenzaldehyde was used instead of4-benzyloxy-5-methoxy-2-nitrobenzaldehyde. MS(M+H)=499.

Examples 7a-7g

The compounds 7a-7g were generally prepared as follows. Compound E (20mg, 0.03 mmoles) was dissolved in acetonitrile (2 ml) containingtriethylamine (17 ul, 0.12 mmoles) and water (0.3 ml). To this was addedthe respective acyl chloride, alkyl chloroformate, or isocyanate (0.03mmoles) and the reaction stirred for 4 hours. The solvent was removed invacuo and the compounds purified by reverse-phase preparative HPLC(acetonitrile/water with 0.1% trifluoroacetic acid) to yield the finalproduct upon lyophilization.

7a:N-[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethyl]-2,2,2-trifluoro-acetamide,MS (M+H)=487.

7b:N-[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethyl]-acetamide,MS (M+H)=433.

7c:N-[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethyl]-butyramide,MS (M+H)=461.

7d:N-[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethyl]-2-chloro-acetamide,MS (M+H)=467.

7e:[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethyl]-carbonicacid methyl ester, MS (M+H)=449.

7f:[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethyl]-carbonicacid isobutyl ester, MS (M+H)=491.

7g:[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethyl]-carbonicacid 2,2,2-trichloro-ethyl ester, MS (M+H)=565

Example 8

The methyl ester of the acid shown above (920 mg 2.85 mmoles) wassuspended in 3/1 THF/water (40 ml) and cooled to 0° C. The solution wastreated with 1 N LiOH (7.1 ml, 7.1 mmoles) and allowed to stirovernight. The reaction was acidified with trifluoroacetic acid untilpH=4.0 was obtained. The solvent was removed in vacuo and the crudematerial purified by flash chromatography (ethyl acetate with 0.5%acetic acid) to yield 1 g of carboxylic acid.

Carbonyl diimidazole (131 mg, 0.8 mmoles) was dissolved in anhydrous THF(1.6 ml) and the carboxylic acid prepared above (251 mg, 0.8 mmoles)added dropwise as a solution in THF (1.6 ml). The reaction was allowedto stir at room temperature for 30 minutes, refluxed for 30 minutes andthen cooled to room temperature again. n-Propylsulfonamide (100 mg) wasadded and stirred for 10 minutes. DBU (123 mg) was added as a solutionin THF (1.6 ml). The reaction was worked up by acidification andextraction into ethyl acetate. The solvent was removed and the crudeproduct purified by flash chromatography (SiO2, ethyl acetate) to yield195 mg of the acyl sulfonamide shown above.

The nitrile prepared above (90 mg, 0.2 mmoles) was dissolved in ethanol(2.5 ml). Diisopropylethylamine (202 mg, 1.56 mmoles) was added followedby hydroxylamine hydrochloride (83 mg, 1.2 mmoles). The reaction washeated to 70° C. for 21 hours. The reaction was cooled and the solventremoved in vacuo. The residue was taken up in 30% acetonitrile/water (4ml) and purified by preparative reverse-phase chromatography(water/acetonitrile 0.1% TFA gradient) to yield 14 mg of thehydroxyamidine shown above.

The hydroxyamidine product was then taken up in ethanol (2 ml) andacetic acid (8 drops). Raney Ni (ca. 100 mg) was added and the reactionstirred vigorously under a hydrogen atmosphere for 2 hours 45 minutes.The product was filtered through Celite and the Celite rinsed first with30% acetonitrile/water containing 0.1% TFA and then with acetonitrile.The solvent was removed in vacuo and the crude product purified bypreparative reverse-phase chromatography (water/acetonitrile 0.1% TFAgradient) to yield the desired product (6 mg). M+H=435.

Example 9 Synthesis of Enantiomerically Pure 6-alkylsulfonylaminoSulfonamides

3-Ethoxy-4-hydroxybenzaldehyde (40 g) was added to dimethylformamide(600 mL) followed by potassium carbonate (40 g, 1.2 Equiv.). Ethyliodide (28.87 mL, 1.5 Equiv.) was added and the solution was heated to60° C. for six hours. The solution was cooled to room temperature andthe solvent was removed under reduced pressure. The solution was dilutedwith ethyl acetate (500 mL), and washed with water, brine, dried withmagnesium sulfate, and evaporated to yield the crude product3,4-ethoxybenzaldehyde (49 g, 104%). The 3,4-ethoxybenzaldehyde (45 g)was dissolved in ethanol (300 mL), and the solution was cooled to 0° C.In a separate flask, potassium hydroxide (19.5 g, 1.5 Equiv.) was addedto ethanol (300 mL) followed by nitromethane (26 g, 1.5 Equiv.) and thesolution was stirred at room temperature for ten minutes and cooled to0° C. This solution was added to the 3,4-ethoxybenzaldehyde and stirredfor 20 minutes and poured onto concentrated hydrochloric acid (200 mL)at 0° C. The ethanol was removed under reduced pressure, and thesolution was diluted with water (300 mL) and the reaction mixture wasextracted with ethyl acetate. The organic layer was dried with magnesiumsulfate and the solvent removed to yield crude product. The crudeproduct was purified by recrystallization with ethyl acetate (47 g,87%). MS (M+H)=238.

The 1-nitro-2-(3,4-diethoxyphenyl)ethylene (16.64 g) and4-aminobenzonitrile (9.12 g, 1.1 Equiv.) were added to tetrahydrofuran(350 mL), and cooled to 0° C. Lithium diisopropylamide (47.8 mL, 1.02Equiv.) was added slowly until a persistent purple color was formed.Zinc (50 g) was added in one portion, followed by acetic acid (35 mL).The solution was warmed to room temperature and stirred for 2 hoursfollowed by the addition of acetic acid (35 mL) and zinc (10 g). Afteran additional 2 hours, acetic acid (25 mL) was added and the reactionmixture was stirred for one hour. Concentrated hydrochloric acid (15 mL)was added and the solution was stirred an additional hour. The solutionwas filtered through a pad of celite and water (250 mL) was added. Thesolution was concentrated to 300 mL under reduced pressure and added tocitric acid (0.5 M, 500 mL) and ethyl acetate/hexane (500 mL). Thecitric acid layer was collected and ammonium hydroxide was added untilthe solution became basic. This solution was extracted with ethylacetate (3×200 mL), and the combined organics were dried with magnesiumsulfate, and evaporated under reduced pressure to yield the crudeproduct. The crude product was diluted with dichloromethane (350 mL) andcooled to 0° C. Phosgene (40.88 mL of a 20% solution in toluene, 1.1Equiv.) was added followed by Hunigs base (24.46 mL, 2 Equiv.). Thesolution was stirred for ten minutes and water (200 mL) was added. Thedichloromethane was collected, dried with magnesium sulfate, andpurified by flash chromatography on silica gel (80% ethyl acetate/20%hexane) to yield the product as a white solid (9.76 g, 40%). MS(M+H)=352.

The 4-[5-(3,4-diethoxyphenyl)-2-oxo-imidazolidin-1-yl-benzonitrile (2.10g) was added to tetrahydrofuran (200 mL) and cooled to −78° C.n-Butyllithium (3.74 mL, 1 Equiv.) was added dropwise, and the solutionstirred for ten minutes. (S)-(+)-2-(6-methoxy-2-naphthyl)propionylchloride (1.49 g, 1 Equiv.) was added in one portion as a solid and thereaction was stirred for one hour. The reaction mixture was warmed toroom temperature, and evaporated under reduced pressure to 50 mL. Thesolution was diluted with ethyl acetate (300 mL), and washed with citricacid (0.5 M), water, brine, and dried with magnesium sulfate. Thesolution was evaporated under reduced pressure and purified by flashchromatography on silica gel (50% ethyl acetate/50% hexane) to yield theproduct4-{5-(3,4-diethoxyphenyl)-3-[2-(6-methoxynaphthalen-2-yl)-propionyl]-2-oxo-imidazolidin-1-yl}-benzonitrileas one diastereomer (1.20 g, 71%). This product was added to methanol(200 mL) followed by lithium hydroxide (1 mL of a 10% aqueous solution)and stirred for fifteen minutes. Acetic acid (10 drops was added, themethanol was removed under reduced pressure and the product was purifiedby flash chromatography on silica gel (80% ethyl acetate/20% hexane) toyield the product (0.71 g, 95%) as a white solid. [α]_(Na) −55.0 (c2.20, acetone). MS (M+H)=352.

The(R)-(-)-4-[5-(3,4-diethoxyphenyl)-2-oxo-imidazolidin-1-yl-benzonitrile(0.710 g) was added to tetrahydrofuran (20 mL) and cooled to −78° C.n-Butyllithium (1.27 mL of a 1.6 M solution in hexane, 1 Equiv.) wasadded dropwise and the solution was stirred for ten minutes.1-Propylsulfonylchloride (0.275 mL, 1.2 Equiv.) was added and thesolution was stirred for fifteen minutes and warmed to room temperature.Acetic acid (10 drops) was added, the solvent removed under reducedpressure, and the product was purified by flash chromatography on silicagel (50% ethyl acetate/50% hexane) to yield the product (0.740 g, 80%).This material (0.300 g) was diluted with dichloroethane (10 mL) andcooled to 0° C. Nitric acid (0.137 mL, 5 Equiv.) was added dropwise andthe solution was stirred for one hour. The solution was diluted withdichloroethane (100 mL), and washed with water, saturated sodiumbicarbonate, dried with magnesium sulfate, and the solvent wasevaporated under reduced pressure. This material was diluted withmethanol (50 mL), and acetic acid (1 mL), and platinum (0.050 g, 5% oncarbon) was added. The solution was hydrogenated for one hour, filteredthrough a pad of celite, and the solvent was evaporated under reducedpressure. This material was dissolved in dichloromethane (5 mL), andHunigs base (0.177 mL, 1.5 Equiv.) and chlorosulfonylacetic acid ethylester (0.189 g, 1.5 Equiv.) was added and the solution was stirred fortwo hours. The solution was purified by direct flash chromatography onsilica gel (50% ethyl acetate/50% hexane) to yield the product (0.160 g)(R)-{2-[3-(4-cyanophenyl)-2-oxo-1-(propane-1-sulfonyl)-imidazolidin-4-yl]4,5-diethoxyphenylsulfamoyl}-aceticacid ethyl ester. MS (M+H)=624.

(R)-{2-[3-(4-cyanophenyl)-2-oxo-1-(propane-1-sulfonyl)-imidazolidin-4-yl]-4,5-diethoxyphenylsulfamoyl}-aceticacid ethyl ester (0.160 g) was diluted with ethanol (5 mL) followed bylithium hydroxide (1 mL of a 10% aqueous solution, 10 Equiv.) and thesolution was stirred for forty eight hours. The solution was purified bydirect flash chromatography on silica gel (20% methanol/80%dichloromethane) to yield the product. This product was diluted withethanol (1 mL) and hydroxylamine (0.035 g, 10 Equiv.) and Hunigs base(0.088 mL, 10 Equiv.) was added and the solution was heated to 60° C.for six hours. The reaction mixture was cooled to room temperature andstirred for twelve hours. Ethanol (3 mL) and acetic acid (0.5 mL), andRaney nickel (0.025 g) was added and the solution was hydrogenated forone hour. The reaction mixture was filtered through a pad of celite andthe solvent was removed under reduced pressure. The product was purifiedby reverse-phase preparative chromatography to yield{2-[1-(4-carbamimidoylphenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4,5-diethoxyphenylsulfamoyl}acetic acid (52 mg). [α]_(Na) −42.1 (c 1.01, methanol) MS (M+H)=587.

Example 10 6-alkoxysubstituted Sulfonamides

Aminoacetonitrile (14.25 g, 92.5 mmoles) was dissolved in1,2-dichloroethane (150 ml) and the reaction was placed under N₂.Triethylamine (32.76 g, 324 mmoles) was added and the reaction wascooled to zero degrees Celsius. A solution of propane-1-sulfonylchloride (13.19 g, 92.5 mmoles) in 1,2-dichloroethane (20 ml) was addeddropwise and the reaction was allowed to warm to room temperature andwas stirred for 16 hours. Thin-layer chromatography showed the presenceof a new product with a higher R_(f). The solvent was removed in vacuoand the crude product was submitted to flash chromatography (methylenechloride:ethyl acetate, 9:1) to yield 10.56 g of propane-1-sulfonic acidcyanomethyl-amide. ¹HNMR (CDCl₃): 5.40 (s, 1H), 4.11 (s, 2H), 3.15 (m,2H), 1.89 (q, 2H), 1.10 (t, 3H).

3-Ethoxy-4-hydroxy-benzaldehyde (Aldrich, 100 g, 0.602 mole) wasdissolved in N,N-dimethylformamide (1 L). The reaction was placed underN₂. Solid potassium carbonate (103 g, 0.662 moles) was added and thereaction was stirred 10 minutes. Iodoethane (175 g, 1.26 moles) wasadded and the reaction was stirred for 16 hours at room temperature. Thereaction was monitored by thin-layer chromatography which indicatedcomplete consumption of the phenol to give a new product. The reactionwas filtered to remove the potassium carbonate and solvent removed invacuo. The residue was dissolved in methylene chloride and filtered.Silica gel (200 g) was added and the dichloromethane removed in vacuo.The crude product absorbed on silica gel was submitted to flashchromatography (hexane, 100%, 2 L, then ethyl acetate:hexane, 1:3, 2 L,then ethyl acetate:hexane, 1:1) to yield 109.36 g of3,4-diethoxy-benzaldehyde ¹HNMR (CDCl₃): 9.83 (s, 1H), 7.41 (m, 2H),6.96 (d, 1H), 4.17 (m, 4H), 1.50 (t, 3H) 1.47 (t, 3H).

3,4-Diethoxy-benzaldehyde (31.45 g, 0.162 moles) was dissolved inmethylene chloride (500 ml). 3-Chloroperbenzoic acid was added and thereaction was heated to reflux for 4 hours. Thin-layer chromatographyshowed consumption of the aldehyde. The reaction was cooled to roomtemperature, diluted with methylene chloride and quenched with saturatedaqueous potassium carbonate. The layers were separated and the aqueoussolution extracted with methylene chloride. The methylene chlorideextracts were combined, washed with water, brine, and dried overanhydrous sodium sulfate, filtered and the solvent was removed in vacuoto yield a crude oil.

The crude oil was dissolved in methanol (300 ml) and a solution of 10%aqueous KOH (60 ml) was added. The reaction was stirred at roomtemperature for 16 hours. Thin-layer chromatography showed consumptionof the intermediate which had formed. The methanol was removed in vacuoand the aqueous solution was acidified with 1.2 N HCl. The solution wasextracted with ethyl acetate. The ethyl acetate extracts were washedwith water and brine, dried over anhydrous sodium sulfate, filtered, andthe solvent removed in vacuo. The residue was submitted to flashchromatography (hexane:ethyl acetate, 3:1) to yield 22.08 g of3,4-diethoxy-phenol. ¹HNMR (CDCl₃): 6.56 (d, 1H), 6.25 (d, 11H), 6.10(dd, 1H), 3.82 (m, 4H), 1.22 (t, 3H), 1.20 (t, 3H).

Nitrobenzene (100 ml) was cooled to zero degrees Celsius and saturatedwith HCl gas. To this solution was added of 3,4-diethoxy-phenol (11.64g, 64 mmoles), propane-1-sulfonic acid cyanomethyl-amide (10.36 g, 64mmoles) and zinc chloride (17.45 g, 128 mmoles). The reaction wasstirred for 1 hour at zero degrees Celsius and then allowed to warm toroom temperature. Stirring was continued for 2 hours. Thin-layerchromatography showed consumption of 3,4-diethoxy-phenol. Water (100 ml)was added cautiously and the reaction was heated to 100 degrees Celsiusfor 1 hour. The reaction was cooled, and extracted with methylenechloride. The extracts were washed with water, brine, dried overanhydrous sodium sulfate, filtered, and the solvent was removed invacuo. The residue was submitted to flash chromatography (2.5-5% ethylacetate in methylene chloride). The purified product was triturated withether, filtered and air dried to yield 17.3 g of propane-1-sulfonic acid[2-(4,5-diethoxy-2-hydroxy-phenyl)-2-oxo-ethyl]-amide. ¹HNMR (CDCl₃):11.86 (s, 1H), 6.93 (s, 1H), 6.46 (s, 1H), 5.26 (t, 1H), 4.55 (d, 2H),4.14 (q, 2H), 4.03 (q, 2H), 3.05 (m, 2H), 1.90 (m, 2H), 1.45 (m, 6H),1.07 (t, 3H).

Propane-1-sulfonic acid[2-(4,5-diethoxy-2-hydroxy-phenyl)-2-oxo-ethyl]-amide (200 mg, 0.579mmoles) was dissolved in tetrahydrofuran (5 ml), placed under N₂, andcooled to zero degrees Celsius. Borane:THF complex (1.74 ml, 1.0 M inTHF, 1.74 mmoles) was added dropwise. The reaction was stirred 15minutes and the allowed to warm to room temperature over 2 hours.Thin-layer chromatography showed consumption of starting material andformation of a new product with a lower R_(f). The reaction was quenchedin 1.2 N aqueous HCl (2.5 ml), diluted with water and extracted withethyl acetate. The extracts were washed with water and brine, dried overanhydrous sodium sulfate, filtered, and the solvent removed in vacuo toyield 190 mg of a crude oil.

The crude oil was dissolved in acetonitrile (5 ml). 4-Aminobenzonitrile(194 mg, 1.64 mmoles) and lithium perchlorate (233 mg, 2.19 mmoles) wereadded. The reaction was heated to 90 degrees Celsius for 3.5 hours thenstirred at room temperature for 18 hours. Thin-layer chromatographyshowed the presence of a new product with a higher R_(f), versus theproduct from the reduction. The reaction was quenched in water andextracted with ethyl acetate. The ethyl acetate extracts were washedwith water and brine, dried over anhydrous sodium sulfate, filtered, andthe solvent removed in vacuo. The residue was submitted to flashchromatography (ethyl acetate:methylene chloride, 1:9) to yield 134 mgof propane-1-sulfonic acid[2-(4-cyano-phenylamino)-2-(4,5-diethoxy-2-hydroxy-phenyl)-ethyl]-amide.¹HNMR (CDCl₃): 7.34 (d, 2H), 6.71 (s, 1H), 6.61 (d, 2H), 6.41 (s, 1H),5.58 (d, 1H), 4.79 (m, 1H), 4.57 (m, 1H), 3.99 (m, 4H), 3.48 (t, 2H),3.00 (m, 2H), 1.80 (q, 2H), 1.41 (t, 3H), 1.34 (t, 3H), 1.03 (t, 3H).

Propane-1-sulfonic acid[2-(4-cyano-phenylamino)-2-(4,5-diethoxy-2-hydroxy-phenyl)-ethyl]-amide(100 mg, 0.223 mmoles) was dissolved in dimethylformamide (1.5 ml) andtreated with solid potassium bicarbonate (22 mg, 0.223 mmoles) followedby ethyl bromoacetate (0.37 ml, 0.223 mmoles). The reaction was stirredunder N₂ for 67 hours. Thin-layer chromatography showed presence of anew product with a higher R_(f). The reaction was quenched in water andextracted with ethyl acetate. The ethyl acetate extracts were washedwith water and brine, dried over anhydrous sodium sulfate, filtered andthe solvent removed in vacuo. The residue was submitted to flashchromatography (ethyl acetate:methylene chloride 1:9) to yield 78 mg of{2-[1-(4-cyano-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]4,5-diethoxy-phenoxy}-aceticethyl ester. ¹HNMR (CHCl₃): 7.35 (d, 2H), 6.81 (s, 1H), 6.57 (d, 2H),6.43 (s, 1H), 4.81 (t, 1H), 4.68 (ABq, 2H), 4.56 (t, 1H), 4.26 (q, 2H),4.05 (q, 2H), 3.95 (m, 2H), 3.54 (t, 2H), 2.98 (m, 2H), 1.80 (m, 2H),1.42 (t, 3H), 1.32 (t, 6H), 1.02 (t, 3H). MS (M+H): 534.

{2-[1-(cyano-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4,5-diethoxy-phenoxy}-aceticacid ethyl ester (76 mg, 0.142 mmoles) was dissolved in tetrahydrofuran(3 ml). Water (1 ml) was added and the reaction was cooled to zerodegrees Celsius. Aqueous LiOH (1.0 M, 0.42 ml, 0.42 mmol) was added tothe reaction. After stirring for 5 minutes, the reaction was allowed towarm to room temperature and was stirred for 16 hours at roomtemperature. The disappearance of the ester was monitored by analyticalhigh pressure liquid chromatography. Additional LiOH (1.0 M, 0.14 ml)was added. The reaction was stirred another 8 hours at room temperature.Consumption of the ester was not complete so freshly prepared LiOH4 (1.0M, 0.14 ml), was added and the reaction stirred 24 hours. More LiOH (1.0M, 0.28 ml) was added and after 67 hours, analytical RP HPLC showedconsumption of the ester (total 1.0 M LiOH=0.98 mL, 6.9 equiv.). Thereaction was acidified with acetic acid and the THF was allowed toevaporate under a stream of N₂. The solution was clarified by additionof acetonitrile and then purified by preparative reverse-phase HPLC(gradient acetonitrile/water with 0.1% trifluoroacetic acid) to yieldafter lyophilization 44 mg of the mono-TFA salt of{2-[1-(cyano-phenylamino)-2-(propane-1-sulfonylamino)ethyl]-4,5-diethoxy-phenoxy}-aceticacid. ¹NMR (CD₃OD): 7.15 (d, 2H), 6.70 (s, 1H), 6.48 (d, 2H), 6.45 (s,1H), 4.76 (t, 1H), 4.60 (s, 2H), 3.85 (q, 2H), 3.73 (m, 2H), 3.43 (dd,1H), 3.26 (dd, 1H partially obscured by the CH3OH solvent peak), 2.76(m, 2H), 1.52 (m, 2H), 1.18 (t, 3H), 1.07 (t, 3H), 0.77 (t, 3H). MS(M+H): 506.

{2-[1-(cyano-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4,5-diethoxy-phenoxy}-aceticacid, mono-TFA salt form (44 mg, 0.071 mmoles) was dissolved in ethanol(1 ml) and treated with diisopropylethylamine (0.89 ml, 0.515 mmoles)and solid hydroxylamine hydrochloride (25 mg, 0.355 mmoles). Thereaction was placed under N₂ and heated to 60 degrees Celsius for 3hours. Analytical high pressure liquid chromatography analysis after 3hours revealed the reaction had not gone to completion. The reactionmixture was cooled to room temperature and stirred at room temperaturefor 16 hours and the progress of the conversion assessed by HPLC. Thereaction mixture was heated at 60 degrees Celsius for 8 hours, stirredat room temperature for 16 hours, heated at 70 degrees for 8 hours andstirred at room temperature for 16 hours. HPLC showed consumption ofstarting material. The reaction was acidified with acetic acid, Raneynickel added and the reaction was hydrogenated at approximately 1 atmunder a balloon of hydrogen for 3 hours. Analytical HPLC showedconsumption of the hydroxy amidine intermediate. The Raney nickelcatalyst was filtered and the solvent was removed in vacuo. The residuepurified by preparative reverse-phase HPLC (gradient acetonitrile/waterwith 0.1% trifluoroacetic acid) to yield after lyophilization 5.6 mg of{2-[1-(carbamimidoyl-phenylamino)-2-(propane-1-sulfonylamino)-ethyl]-4,5-diethoxy-phenoxy}-aceticacid, bis-TFA salt form. MS (M+H): 523.

Example 11 6-alkylsulfonyl-alkyl-amino Substituted AcylsulfonamideSynthesis

4,5 diethoxy-2-nitrobenzaldehyde (55.5 g 206 mmoles) and4-aminobenzonitrile (23 g, 195 mmoles) were dissolved in methanol (700ml) and stirred at 60° C. for 2 hours. The reaction was allowed to coolto 0° C. and tosylmethylisonitrile (45 g. 230 mmoles) added. Borontrifluoroetherate (78 ml, 620 mmoles) was added dropwise over 10minutes. The reaction was stirred at 0° C. for 30 minutes, allowed tocome to room temperature and then stirred at ambient temperature for 1.5hours. Water (18 ml) was added and the mixture stirred at roomtemperature overnight. The following day the methanol was removed invacuo and the residue taken up in ethyl acetate. The organic layer waswashed with water and then dried over anhydrous sodium sulfate. Thesodium sulfate was filtered off and the ethyl acetate removed in vacuo.The crude material was submitted to flash chromatography (hexanes:ethylacetate, 2:1 then 1:1) to yield 46 g of the desired product(4-ethoxy-5-ethoxy-2-nitro-phenyl)-(4-cyano-phenylamino)acetic acidmethyl ester.

(4-ethoxy-5-ethoxy-2-nitro-phenyl)-(4cyanophenylamino)acetic acid methylester (11 g, 27.5 mmole) was dissolved in ethyl acetate (300 m) andadded to a flask containing 5% Pt/C (3 g) under a nitrogen atmosphere.The nitrogen was removed and replaced by hydrogen (balloon) and thereaction stirred vigorously for 6 hours. The catalyst was filtered offand the solvent removed in vacuo. The residue was taken up indichloromethane (ca. 300 ml) and pyridine (5.6 ml, 70 mmole) added. Thereaction was cooled to 0° C. and methanesulfonyl chloride (2.5 ml, 33mmole) added dropwise. The reaction was stirred overnight. The solutionwas washed with water and the solvent removed in vacuo. The crudeproduct was chromatographed on silica using flash chromatography(Hexane:ethyl acetate 1:1) to yield 5 g of desiredmaterial—(4-cyano-phenylamino)-[4,5-diethoxy-2-(methanesulfonylamino)-phenyl]-aceticacid methyl ester. The product from about(4-cyano-phenylamino)-4,5-diethoxy-2-methanesulfonylamino-phenyl)-aceticacid methyl ester (5 g, 10.7 mmoles) was dissolved in dry DMF (100 ml)and cesium carbonate (7.25 g, 22 mmoles) and iodomethane (1 ml, 16mmoles) added. The reaction was stirred at room temperature for 3 hoursand the solvent removed in vacuo. The residue was taken up in ethylacetate, acidified with 1N hydrochloric acid and the organic layerwashed once with water. The material was dried over anhydrous sodiumsulfate and the solvent removed in vacuo. The residue was flashchromatographed (hexane:ethyl acetate, 1:1) to yield 2.6 g of desiredmaterial—(4-cyano-phenylamino)-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)-phenyl]-aceticacid methyl ester.

The(4-cyano-phenylamino)-4,5-diethoxy-2-methanesulfonyl-methyl-amino-phenyl)-aceticacid methyl ester obtained above (2.6 g, 5 mmole) was dissolved inmethanol. 1 N LiOH was added (25 ml) and the reaction stirred at roomtemperature for 5 hours. The methanol was removed in vacuo and thereaction was acidified with 1 N hydrochloric acid. The product wasextracted into ethyl acetate and washed with water. Flash chromatography(Ethyl acetate with 5% acetic acid) yielded 1.9 g the desiredacid—(4-cyano-phenylamino)-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)-phenyl]-aceticacid.

The(4-cyano-phenylamino)-4,5-diethoxy-2-methanesulfonyl-methyl-amino-phenyl)-aceticacid obtained above (350 mg, 0.75 mmole) was combined with carbonyldiimidazole (610 mg, 3.77 mmole) in dry THF (6 ml). The reaction washeated at 60° C. for 1 hour and cooled to room temperature. To thissolution was added phenylsulfonamide (650 mg, 4.14 mmole) and DBU (5mmole) as a solution in 5 ml THF. The reaction was stirred for 3 hoursand the THF removed in vacuo. The residue was taken up in ethyl acetateand acidified with 1 N hydrochloric acid. The organic layer wasseparated, washed with water and dried over anhydrous sodium sulfate.The crude product was purified by flash chromatography (Hexanes:ethylacetate 1:1 then ethyl acetate with 5% acetic acid) to yield 302 mg ofdesiredproduct—-N-{(4-cyano-phenylamino)-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)-phenyl]-acetyl}benzenesulfonamide.

TheN-{(4-cyanophenylamino)-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)-phenyl]-acetyl}benzenesulfonamideobtained above (126 mg, 0.21 mmole) was dissolved in ethanol (1.8 ml)and heated to 60° C. Diisopropylethylamine (DIPEA—260 ul, 1.5 mmole) wasadded followed by hydroxylamine-hydrochloride (74 mg, 1.04 mmole). Thereaction was stirred at 60° C. under a nitrogen atmosphere for 6 hours.The reaction was then allowed to cool to room temperature. The solutionwas diluted with methanol (5 ml) and acetic acid (2 ml) and Raney Nickel2800 (ca. 50 mg) added as a suspension. The reaction was then stirredvigorously under a hydrogen atmosphere for 1 hour. The catalyst wasfiltered off and the solvent removed. The crude product was purified bypreparative reverse-phase HPLC using a water-acetonitrile (0.1% TFA)gradient to yield 40 mg of desired4-{2-benzenesulfonylamino-1-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)phenyl]-2-oxo-ethylamino}benzamidineas its trifluoroacetic acid salt. MS: (M+H)=604.

Example 12

4-isopropoxy-5-ethoxy-benzaldehyde (10.6 g 50 mmoles) and4-aminobenzonitrile (5.9 g, 50 mmoles) were dissolved in methanol (150ml) and stirred at 60° C. for 1.6 hours. The reaction was allowed tocool to 0° C. and tosylmethylisonitrile (9.75 g. 50 mmoles) added. Borontrifluoroetherate (19 ml, 150 mmoles) was added dropwise over 10minutes. The reaction was stirred at 0° C. for 30 minutes, allowed tocome to room temperature and then stirred at ambient temperature for 1.5hours. Water (4.5 ml) was added and the mixture stirred at roomtemperature 2 days. The methanol was removed in vacuo and the residuetaken up in ethyl acetate. The organic layer was washed with water andthen dried over anhydrous sodium sulfate. The sodium sulfate wasfiltered off and the ethyl acetate removed in vacuo. The crude materialwas submitted to flash chromatography (hexanes:ethyl acetate, 1:1) toyield 12.5 g of the desired product(4-isopropoxy-5-ethoxy-phenyl)-(4-cyano-phenylamino)-acetic acid methylester.

The product from above,(4-isopropoxy-5-ethoxy-phenyl)-(4-cyano-phenylamino)-acetic acid ethylester, (6 g, 16.3 mmole) was treated with 1 N LiOH (ca. 50 ml) in THF(ca. 150 ml). The reaction was stirred at room temperature for 6 hoursand acidified with 1 N hydrochloric acid. The THF was removed in vacuoand the product extracted into ethyl acetate. The crude material waspurified by reverse phase chromatography (ethyl acetate 3% acetic acid)to yield 4.85 g of desiredacid—(4-isopropoxy-5-ethoxy-phenyl)-(4-cyano-phenylamino)-acetic acid.

The (4-isopropoxy-5-ethoxy-phenyl)-(4-cyano-phenylamino)-acetic acidobtained above (200 mg, 0.57 mmole) was combined with carbonyldiimidazole (200 mg, 1.2 mmole) in dry THF (4 ml). The reaction wasallowed to stir at room temperature for 1 hour. To this solution wasadded the corresponding alkyl or arylsulfonamide (2.2 mmole) and DBU(2.2 mmole) as a solution in 3 ml THF. The reaction was stirredovernight and the THF removed in vacuo. The residue was taken up inethyl acetate and acidified with acetic acid. The organic layer wasseparated, washed with water and dried over anhydrous sodium sulfate.The crude product was purified by flash chromatography (Hexanes:ethylacetate 1:2) to yield desired product—N-{(4-cyano-phenylamino)-[4isopropoxyl,5-ethoxy-phenyl]-acetyl}(alkyl or aryl) sulfonamide.

The N-{(4-cyano-phenylamino)-[4isopropoxyl-5-ethoxy-phenyl]-acetyl}(alkyl or aryl) sulfonamide obtainedabove (ca. 0.24 mmole) was dissolved in ethanol (1-3 ml) and heated to60° C. Diisopropylethylamine (DIPEA—260 ul, 1.5 mmole, 6 eq.) was addedfollowed by hydroxylamine-hydrochloride (84 mg, 1.25 mmole, 5 eq.). Thereaction was stirred at 60° C. under a nitrogen atmosphere for ca. 6hours. The reaction was then allowed to cool to room temperature. Thesolution was diluted with methanol (5 ml) and acetic acid (2 ml) andRaney Nickel 2800 (ca. 50 mg) added as a suspension. The reaction wasthen stirred vigorously under a hydrogen atmosphere for 1-6 hours. Thecatalyst was filtered off and the solvent removed. The crude productswere purified by preparative reverse-phase HPLC using awater-acetonitrile (0.1% TFA) gradient or by flash chromatography (ethylacetate:acetone:water:acetic acid, 6:2:1:1) to yield the desired4-{2-(alkyl or aryl)sulfonylamino-1-[4-isopropoxy,5-ethoxy)-phenyl]-2-oxo-ethylamino}benzamidineas its trifluoroacetic acid or acetic acid salt.

Using an analogous procedure, the following compounds having differentR₁ groups were prepared:

R₁=ethyl:4-{2-ethylsulfonylamino-1-[4-isopropoxy,5-ethoxy)-phenyl]-2-oxo-ethylamino}benzamidine:MS(M+H)=463.

R₁=n-propyl:4-{2-propylsulfonylamino-1-[4-isopropoxy,5-ethoxy)-phenyl]-2-oxo-ethylamino}benzamidine:MS(M+H)=477.

R₁=n-butyl:4-{2-butylsulfonylamino-1-[4-isopropoxy,5-ethoxy)-phenyl]-2-oxo-ethylamino}benzamidine:MS(M+H)=491.

R₁=CH₂CH₂CO₂Me:3-[(4-carbamimidoyl-phenylamino)-(3-ethoxy-4-isopropoxy-phenyl)-acetylsufamoyl]-propionicacid methyl ester: MS(M+H)=521.

R₁=phenyl:4-{2-benzenesulfonylamino-1-[4-isopropoxy,5-ethoxy)-phenyl]-2-oxo-ethylamino}benzamidine:MS(M+H)=511.

Example 13 Acylsulfonamide with Substitution on the AminobenzamidineRing

2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF(200 ml). Potassium carbonate (11 g. 80 mmole) and benzyl bromide (9 ml,75 mmole) were added. The reaction was stirred at room temperatureovernight. The DMF was removed in vacuo and the residue taken up inethyl acetate and water. The organic layer was separated, washed with 1N NaOH, then with water, and dried over sodium sulfate. The crudeproduct (5 g) was dissolved in ethyl acetate (75 ml) and added to aflask containing 5% Pt/C (500 mg). The reaction was placed under ahydrogen atmosphere (balloon) and stirred vigorously for several hoursuntil the reaction was done (TLC). The catalyst was filtered off and thesolvent removed. The product was purified by flash chromatography toyield 4.12 g of 4-amino, 2-benzyloxybenzonitrile.

4,5-diethoxy-benzaldehyde (3.6 g, 17.8 mmole) and4-amino-2-benzyloxybenzonitrile (3.7 g, 17.8 mmole) were dissolved inmethanol (40 ml) and stirred for 2 hours. Tosylmethylisonitrile (3.48 g.17.8 mmoles) was added. The reaction was cooled to 0° C. and borontrifluoroetherate (6.7 ml, 54 mmoles) was added dropwise. The reactionwas stirred at 0° C. for 30 minutes, allowed to come to room temperatureand then stirred at ambient temperature for 3.5 hours. Water (1.6 ml)was added and the mixture stirred at room temperature 2 days. Themethanol was removed in vacuo and the residue taken up in ethyl acetate.The organic layer was washed with water and then dried over anhydroussodium sulfate. The sodium sulfate was filtered off and the ethylacetate removed in vacuo. The crude material was submitted to flashchromatography (hexanes:ethyl acetate, 4:1) to yield 4.2 g of thedesired product(3-benzyloxy-4-cyano-phenylamino)-3,4-ethoxy-phenyl-)-acetic acid methylester.

The product from above was treated with LiOH (1.96 g) in water (50 ml)methanol (100 m), and THF (50 ml). The reaction was stirred at roomtemperature for 3 hours and acidified with acetic acid. The solvent wasremoved in vacuo and the product extracted into ethyl acetate. The crudematerial was purified by reverse phase chromatography (ethyl acetate 3%acetic acid) to yield 5 g of desired acid—product(3-benzyloxy-4-cyano-phenylamino)-3,4-ethoxy-phenyl-)-acetic acid.

(3-benzyloxy-4-cyano-phenylamino)-3,4-ethoxy-phenyl-)-acetic acid (750mg, 1.68 mmoles) was dissolved in dry THF (3 ml) and carbonyldiimidizole (CDl—545 mg, 3.36 mmoles) was added. The reaction was heatedto 40 degrees for 1 hour then cooled to room temperature. To this wasadded a solution of benzenesulfonamide (1.05 g, 6.7 mmoles), DBU (1.02 g6.72 mmoles) in THF (3 ml). The reaction was stirred overnight and then1 N hydrochloric acid was added. The THF was removed in vacuo and theproduct purified by flash chromatography (ethyl acetate 2% acetic acid)to yield the desired product. This material (215 mg) was dissolved inethanol (5 ml) containing acetic acid (1 drop) and added to 5% Pd/C (100mg). The reaction was placed under a hydrogen atmosphere and stirredvigorously until the reaction was complete. The catalyst was filteredoff and than solvent removed in vacuo. The crude product was purified byflash chromatography to yield 150 mg of desiredproduct—N-[(3-hydroxy-4-cyano-phenylamino)-(3,4-diethoxy-phenyl-acetyl]benzenesulfonamide.

TheN-[(3-hydroxy-4-cyano-phenylamino)-(3,4-diethoxy-phenyl-acetyl]benzenesulfonamideobtained above (75 mg, 0.15 mmoles) was dissolved in ethanol (2 ml ml)and heated to 60° C. Diisopropylethylamine (DIPEA—185 ul, 1 mmole) wasadded followed by hydroxylamine-hydrochloride (53 mg, 0.75 mmole). Thereaction was stirred at 60° C. under a nitrogen atmosphere for ca. 6hours. The reaction was then allowed to cool to room temperatureovernight. The solution was diluted with acetic acid (1 ml) and methanol(1 ml). Raney Nickel 2800 (ca. 50 mg) was added as a suspension. Thereaction was then stirred vigorously under a hydrogen atmosphere for 0.5hours. The catalyst was filtered off and the solvent removed. The crudeproducts were purified by preparative reverse-phase HPLC using awater-acetonitrile (0.1% TFA) gradient to yield the desired amidineproduct—4-[2-benzenesulfonylamino1-(3,4diethoxy-phenyl)-2-oxo-ethylamino]-2-hydroxybenzamidine. MS (M+H)=513.

Using an analogous procedure, the corresponding halogen containingcompounds can be made from 2-chloro-4-nitro-benzonitrile and2-bromo-4-nitro-benzonitrile.

Example 14 Tissue Factor/Factor VIIa Antagonist Assay

This procedure can be used to determine the constant of inhibition (Ki)for a sample compound of the invention.

Materials:

Assay Buffer: 100 mM Hepes pH 7.8, 140 mM NaCl, 0.1% PEG-8000, 0.02%Tween-80, 5mM CaCl₂

Coagulation

Factor: recombinant human factor VIIa (NB #25942-16) Cofactor: solubleTissue Factor (1-219) Substrate: Chromozym-tPA (Boehringer Mannheim,Cat. #1093 037) Reconstitute at 20 mM in H₂O. Dilute to 4 mM in assaybuffer with CaCl₂ prior to use. Samples: Dilute samples to 3% DMSO inassay buffer (lacking CaCl₂).

Procedure:

1. Prepare a solution of 2 μg/mL (90 nM) tissue factor and 1.5 μg/mL (30nM) factor VIIa in assay buffer with CaCl₂.

2. Incubate for 15 minutes at room temperature.

3. Add 50 μL sample to each well.

4. Add 50 μL tissue factor/factor VIIa solution to each well.

5. Incubate for 15 minutes at room temperature with gentle agitation.

6. Add 50 μL substrate to each well.

7. Agitate plate for 20-25 sec.

8. Monitor absorbance at 405 nM every 10 sec for a total of 5 minutes atroom temperature.

9. Calculate Vmax over 10 points.

Example 15 Factor Xa, Thrombin, and Plasma Kallikrein Assays

These procedures can be used to determine the constant of inhibition(Ki) for a sample compound of the invention.

Materials:

Assay Buffer: 100 mM Hepes pH 7.8, 140 mM NaCl, 0.1% PEG-8000, 0.02%Tween-80 human Factor Xa, Thrombin, or Plasma Kallikrein (HematologicTechnologies) Coagulation Factor: Dilute to 0.45 μg/mL (9.8 nM) in assaybuffer. Substrate: S-2222, S2366 or S2302 -(See below - ChromogenixInc,) Reconstitute at 5 mM in H2O. Dilute to 1.5 mM in assay bufferprior to use. Samples: Dilute samples to 3% DMSO in assay buffer.

Procedure:

1. Add 50 μL sample to each well.

2. Add 50 μL appropriately diluted coagulation factor to each well.

3. Incubate for 5 minutes at room temperature with gentle agitation.

4. Add 50 μL appropriately diluted substrate to each well.

5. Agitate plate for 20-25 sec.

6. Monitor absorbance at 405 nM every 10 sec for a total of 5 minutes atroom temperature.

7. Calculate Vmax over 10 points.

Assay—Enzyme, Substrate and Final Concentrations

Assay TF/FVIIa FXa Thrombin PlasmaKallikrein Coag Factor 100 nM FVIIa3.3 nM 8.2 nM 1.5 nM Final 30 nM TF concentration Substrate ChromozymeS-2222 S-2366 S-2302 tPA Final Conc. 1.33 mM 0.5 mM 0.3 mM 0.3 mM ofSubstrate

What is claimed is:
 1. A compound having the structure shown below:

where A and B are independently CH, CR₃ or N; X is C═O or(CR_(4a)R_(4b))_(m) where m=1 or 2; Y is S(O)_(n)—R₁ where n=1 or 2,S(O)_(n)—NR₂R₂ where n=1 or 2, S(O)_(n)—OR₂ where n 1 or 2, C(O)R₁,C(S)R₁, C(O)—OR₁, C(O)—NR₂R₂; N₁ and N₂ are nitrogen atoms; Q and R₁ areindependently (1) optionally substituted alkyl having 1 to about 10carbon atoms; (2) optionally substituted aralkyl containing an arylmoiety having 6 to about 10 ring carbon atoms bonded to an alkyl moietycontaining 1 to about 10 carbon atoms; (3) optionally substitutedheteroaralkyl containing a heteroaryl moiety having 5 to about 10 ringatoms bonded to an alkyl moiety having 1 to about 10 carbon atoms; (4)optionally substituted carbocycloalkyl containing a carbocyclyl moietyhaving 3 to about 10 ring carbon atoms bonded to an alkyl moiety having1 to about 10 carbon atoms; (5) optionally substituted heterocycloalkylcontaining a heterocyclyl moiety having 3 to about 10 ring atoms bondedto an alkyl moiety having 1 to about 10 carbon atoms; (6) optionallysubstituted alkenyl having 2 to about 10 carbon atoms; (7) optionallysubstituted aralkenyl containing an aryl moiety having 5 to about 10ring atoms bonded to an alkenyl moiety having 2 to about 10 carbonatoms; (8) optionally substituted heteroaralkenyl containing aheteroaryl moiety having 5 to about 10 ring atoms bonded to an alkenylmoiety having 2 to about 10 carbon atoms; (9) optionally substitutedcarbocycloalkenyl containing a carbocyclyl moiety having 3 to about 10ring carbon atoms bonded to an alkenyl moiety having 2 to about 10carbon atoms; (10) optionally substituted heterocycloalkenyl containinga heterocyclyl moiety having 3 to about 10 ring atoms bonded to analkenyl moiety having 2 to about 10 carbon atoms; (11) optionallysubstituted aryl having 6 to about 10 ring carbon atoms; (12) optionallysubstituted heteroaryl having 5 to about 10 ring atoms with ring atomsselected from carbon atoms and heteroatoms, where the heteroatoms arenitrogen, oxygen or sulfur; (13) optionally substituted carbocyclylhaving 3 to about 10 ring carbon atoms; (14) optionally substitutedheterocyclyl having 3 to about 10 ring atoms with ring atoms selectedfrom carbon atoms and heteroatoms, where the heteroatoms are nitrogen,oxygen or sulfur; each R₂ is, independently, H, alkyl, substitutedalkyl, C(O)R₇ or C(NH)R₇, or N₁R₂ and N₂R₂ are together form the groupN₁—CO—N₂; R₃ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen or OH; R_(4a) andR₅ are, independently, a member selected from the group consisting of H,unsubstituted or substituted alkyl, unsubstituted or substitutedalkoxyalkyl, unsubstituted or substituted haloalkyl, unsubstituted orsubstituted aryl, alkyl-OR₇, alkyl-NR₇R₈, alkyl-OC(O)R₇, alkyl-C(O)OR₇,alkyl-C(O)R₇OC(O)R₇, C(O)OR₇, C(O)R₇ and members in which the alkyl, R₇or R₈ is substituted with 1-3 F, Cl, Br, I, OR₇, SR₇, NR₇R₈, OC(OR₇),C(O)OR₇, C(O)R₇, C(O)NR₇R₈, NHC(NH)NH₂, PO₃, unsubstituted orsubstituted indolyl or unsubstituted or substituted imidazolyl groups;R_(4b) is H, alkyl, or substituted alkyl; R₆ is selected from the groupselected from H, C₁-C₆ alkyl, C₁-C₆ alkyl-OR₇, C₁-C₆ alkyl-N R₇R₈, C₁-C₆haloalkyl, halo, cyano, OR₇, SR₇, NR₇R₈, C(O)OR₇, C(O)R₇ and OC(O)R₇; R₇and R₈ are independently H or C₁-C₆ alkyl; and acid and base additionsalts and prodrugs thereof.
 2. The compound of claim 1, wherein Q isphenyl optionally substituted with 1-5 substituents selected from thegroup consisting of halo, nitro, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, NR₇R₈, OR₇, SR₇, C₁-C₆ alkyl-C(O)OR₇, OC₁-C₆ alkyl-C(O)OR₇,C₁-C₆ alkyl-OR₇, OC₁-C₆ alkyl-OR₇, C₁-C₆ alkyl-NR₇R₈, OC₁-C₆alkyl-NR₇R₈, C₁-C₆ alkyl-C(O)NR₇R₈, OC₁-C₆ alkyl-C(O)NR₇R₈, C₁-C₆alkly-C(O)R₇, OC₁-C₆ alkyl-C(O)R₇, C₁-C₆ haloalkyl, O-aralkyl, C(O)OR₇,C(O)NR₇R₈, OC(O)NR₇R₈, NHC(O)R₇, NHC(O)NR₇R₈, NR₇S(O)_(n)R₁,NR₇S(O)_(n)R₇, S(O)_(n)R₇, S(O)_(u)NR₇, where R₇ and R₈ independentlyare H or C₁-C₆ alkyl.
 3. The compound of claim 1, wherein Q has thestructure

wherein R₉ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, hydroxy, NR₇R₈, SR₇ or OR₇, where R₇ and R₈, independently, areH or unsubstituted or substituted C₁-C₆ alkyl; R₁₀, R₁₁ and Z₂,independently, are each selected from the group consisting of H, halo,nitro, cyano, C₁-C₆ alkyl, C₆-C₁₀ aryl, NR₇R₈, OR₇, SR₇, C₁-C₆alkyl-C(O)R₇, C₁-C₆ alkyl-C(O)NR₇R₈, C₁-C₆ alkyl-C(O)OR₇, C₁-C₆alkyl-OC(O)R₇, C₁-C₆ alkyl-OR₇, OC₁-C₆ alkyl-C(O)R₇, OC₁-C₆alkyl-C(O)OR₇, OC₁-C₆ alkyl-OC(O)R₇, O—C₁-C₆ alkyl-OR₇, OC₁-C₆alkyl-C(O)NR₇R₈, C₁-C₆ haloalkyl, OR₁₂, C₁-C₆ alkyl-R₁₂, O—C₁-C₆alkyl-R₁₂, C(O)OR₇, C(O)OR,₂, C(O)NR₇R₈, OC(O)NR₇R₈, NR₇C(O)R₇,NR₇C(O)R₁₂, NR₇C(O)—NR₇R₈, NR₇C(O)OR₇, NR₇C(O)OR₁₂, NR₇S(O)n—R₁,NR₇S(O)n—R₇ and NR₇S(O)_(n)—R₁₂, where R₇ and R₈, independently, are Hor unsubstituted or substituted C₁-C₆ alkyl, R₁₂ is unsubstituted orsubstituted C₆-C₁₀ aryl or heterocycl as defined above and n is 1 or 2;Z₁ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen or nitro.
 4. The compound ofclaim 1, wherein R₁₀ is selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ aminoalkyl, C₁-C₆ haloalkyl, C₁-C₆hydroxyalkyl, phenyl, phenoxy, benzyl, benzyloxy, as well as phenoxy-and benzyloxy-substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halo, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ aminoalkyl, OC(O)—C₁-C₆ alkyl,C(O)O—C₁-C₆ alkyl and C(O)OH.
 5. The compound of claim 3, wherein R₁₁ isNR₇C₁-C₆ alkyl-C(O)NR₇R₈, NR₇S(O)n—R₇ or N R₇S(O)n—R₁₂, n is 1 or 2and/or where Z₁=Z₂=H and/or where R₁₀ is OR₇, OR₁₂, OC₇-C₁₀-aralkyl,OC₁-C₆ alkyl-OR₇ or OC₁-C₆ alkyl-OR₁₂.
 6. The compound of claim 3,wherein Z₁ and Z₂ are hydrogen; Z₁, Z₂ and R₁₁ are hydrogen; or Z₁, R₁₀and R₁₁ are hydrogen.
 7. The compound of claim 3, wherein Z₁ or Z₂ isC₁-C₆ alkyl, C₁-C₆ alkoxy, halogen or nitro.
 8. The compound of claim 3,wherein R₁₀ is OR₇, OR₁₂, C₁-C₆ alkyl-OR₇ or C₁-C₆ alkyl-OR₁₂.
 9. Thecompound of claim 3, wherein Y is S(O)_(n) R₁ where n=1 or 2 and R₁₁ isNR₇S(O)_(n)—R₇ or NR₇S(O)_(n)—R₁₂, n is 1 or
 2. 10. The compound ofclaim 3, wherein R₁₀ and Z₂ or Z₂ and R₁₁ are bonded together to form afused unsubstituted or substituted, carbocyclic or hetercyclic ring. 11.The compound of claim 1, wherein X is a carbonyl group.
 12. The compoundof claim 1, wherein R₁ is selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, naphthyl,benzyl and heteroaryl having 5-6 ring atoms selected from carbon atomsand 1-2 heteroatoms, where the heteroatoms are N, S, or O, and R₁optionally substituted with 1-3 substituents selected from the groupconsisting of halo, nitro, C₁-C₆ alkyl, NR₇R₈, OR₇, SR₇, C₁-C₆alkyl-C(O)OR₇, C₁-C₆ alkyl-OC(O)R₇, C₁-C₆ alkyl-C(O)R₇, C₁-C₆ alkyl-OR₇,C₁-C₆ haloalkyl, C₁-C₆ alkyl-NR₇R₈, C(O)OR₇, OC(O)R₇, C(O)NR₇R₈,OC(O)NR₇R₈, NHC(O)R₇, and NHC(O)NR₇R₈, where R₇ and R₈ independently areH or C₁-C₆ alkyl.
 13. The compound of claim 1, wherein A and B are CH.14. The compound of claim 1, wherein R₆ is H.
 15. The compound of claim1, wherein Y is S(O)_(n)R, where n=1 or
 2. 16. A composition, comprisingthe compound of claim 1 and a carrier or excipient.
 17. A method ofinhibiting TF/factor VIIa, factor Xa, thrombin or kallikrein activity,comprising contacting TF/factor VIIa factor Xa, thrombin or kallikreinwith an effective amount of the composition of claim
 16. 18. A method oftreating a TF/factor VIIa, factor Xa, thrombin or kallikrein mediateddisorder, comprising administering to a mammal in need thereof aneffective amount of the composition of claim
 16. 19. A method ofpreventing thrombosis or treating abnormal thrombosis, comprisingadministering to a mammal in need thereof an effective amount of thecomposition of claim 16.